The Interaction Between Contactin and Amyloid Precursor Protein and Its Role in Alzheimer’s Disease

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The Interaction Between Contactin and Amyloid Precursor Protein and Its Role in Alzheimer’s Disease

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Rosemary A. Bamford, a Jocelyn Widagdo, b,c Natsuki Takamura, a,d Madeline Eve, a Victor Anggono b,c and Asami Oguro-Ando a*

6

a

7

b

Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro, Tokyo, Japan

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c

Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Qld, Australia

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d

Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro, Tokyo, Japan

2

11 10

University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, UK

Abstract—Alzheimer’s disease (AD) is a debilitating disease and the most common cause of dementia. As the world population ages even modest advances in therapies and preventative strategies would be of benefit. The specific physiological function of the amyloid precursor protein (APP) remains unclear despite strong genetic and biochemical evidence of APP involvement in AD. The intricate molecular processes of the nervous system rely on interactions between cell surface receptors coupled to intracellular downstream signaling networks. APP is an integral membrane protein which interacts with members of the Contactin family of proteins. Here we review recent progresses in the field and discuss the physiological importance of APP-Contactin interaction, as well as their roles and contributions in the pathophysiology of AD. Ó 2019 IBRO. Published by Elsevier Ltd. All rights reserved.

Key words: Alzheimer’s disease, Contactin, amyloid precursor protein, synaptic plasticity.

INTRODUCTION

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Dementia and Alzheimer’s disease

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Dementia is a group of age-related brain diseases that include primary neurological and neuropsychiatric symptoms. They are classically recognized as diseases of memory, and studies have mainly focused on investigating the memory-associated brain defects. Alzheimer’s disease (AD), the most common neurodegenerative disorder causing dementia later in life, is a chronic disorder characterized by progressive neuropathology and cognitive decline, and accounts for

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*Corresponding author. Address: University of Exeter Medical School, RILD Building, Royal Devon & Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK. E-mail address: [email protected] (A. Oguro-Ando). Abbreviations: AD, Alzheimer’s disease; AICD, amyloid precursor protein intracellular cytoplasmic domain; AMPA(R), a-amino-3-hydrox y-5-methyl-4-isoxazolepropionic acid (receptor); Ab, amyloid b-peptide; APLP, amyloid precursor-like protein; APP, amyloid precursor protein; APPL, amyloid precursor protein like; ASD, autism spectrum disorder, BACE1, b-secretase 1; CAM, cell adhesion molecule; CNTN, Contactin; CNTNAP, Contactin-associated protein-like; CSF, cerebrospinal fluid; GC, growth cone; GWAS, genome-wide association study; IgCAM, immunoglobulin cell adhesion molecule; LOAD, late-onset Alzheimer’s disease; N(g)CAM, neural-(glia) cell adhesion molecule; NMDA, N-methyl-D-aspartate; PTPR, protein tyrosine phosphatase; sAPPa/b, soluble alpha/beta-APP; SNP, single nucleotide polymorphism; SUA, serum uric acid; VGKC, voltage-gated potassium channel.

60–80% of dementia cases (Masters et al., 2015). It affects in excess of 26 million people worldwide (Brookmeyer et al., 2007; Prince et al., 2014). It is projected that by 2050 this number will increase to 106.2 million, with 1 in 85 persons living with AD and 62% of cases estimated to be female (Brookmeyer et al., 2007). As the world’s population ages, we will face a looming financial and social burden due to AD epidemic (Wimo et al., 2006). Despite scientific research extending our knowledge on the cellular and molecular bases of dementia, therapies are still limited as the underlying pathomechanisms are poorly understood. The impact of an aging population is complex and multifaceted, making it an incredibly challenging social situation. National reports in both the US and the UK indicate that Alzheimer’s and dementia are among the most feared diseases associated with the elderlies (Harris Interactive for MetLife Foundation (2011) What America Thinks: MetLife Foundation Alzheimer’s Survey, MetLife Foundation). This needs to be addressed soon for our future public health care needs.

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Amyloid precursor protein (APP)

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Amyloid precursor protein (APP) is a single-pass type I transmembrane glycoprotein with a large extracellular domain (Fig. 1A). The specific physiological function of APP remains uncertain, however APP is known to play an important role in neural growth, migration and

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https://doi.org/10.1016/j.neuroscience.2019.10.006 0306-4522/Ó 2019 IBRO. Published by Elsevier Ltd. All rights reserved. 1 Please cite this article in press as: Bamford RA et al. The Interaction Between Contactin and Amyloid Precursor Protein and Its Role in Alzheimer’s Disease. Neuroscience (2019), https://doi.org/10.1016/j. neuroscience.2019.10.006

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Fig. 1. Model structure of APP, Contactin and CNTNAP family proteins. (A) APP is made up of an N-terminal E1, an acidic (A) and a central APP (E2) domain. APLP1/2 share a similar structure to APP. (B) Contactins consist of multiple extracellular immunoglobulin (horseshoes) and fibronectin type III (rectangles) domains that are anchored to the plasma membrane by glycosylphosphatidylinositol (GPI). (C) CNTNAP proteins (1–4) are similar in structure with fibrinogen-like (FBG) (red filled squares); EGF-like domain (blue filled circles), laminin globular-like domains (Lam. G) and coagulation factor 5/8 type C VIII (F VIIIC)/discoidin domain (yellow filled ovals). CNTNAP1 contains a Pro-Gly-Tyr rich sequence (green filled square). CNTNAP1 and CNTNAP2 have a specific juxtamembrane region (pink filled rectangle) and CNTNAP2-4 have PDZ-binding sites (a series of imperfect Pro-Gly-Tyr-Xxx repeats) (green filled circle). Little is known about the structure of CNTNAP5. CNTNAP schematic adapted from (Denisenko-Nehrbass et al., 2003; Zou et al., 2017). Interactions between domains are highlighted with blue brackets and arrow. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

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maturation during different stages of brain development (Jacobsen and Iverfeldt, 2009; Ludewig and Korte, 2017; Mu¨ller and Zheng, 2012; Pramatarova et al., 2008; Young-Pearse et al., 2008). In particular, APP is highly expressed in the developing cortex during differentiation/ migration of cortical neurons, suggesting an important role in neuronal development (Nicolas and Hassan, 2014; van der Kant and Goldstein, 2015; Young-Pearse et al., 2007). APP also has a role in axonal outgrowth during neurodevelopment. The axonal growth cone (GC) has the important task of steering axons through cytoskeleton dynamics, membrane expansion and balancing cell adhesion. APP is highly enriched and enables axonal GC function by acting as an adhesion molecule (Sosa et al., 2017, 2013). Overexpression of APP and its effect on neuronal and synaptic defects has previously been investigated in Down syndrome individuals due to the extra copy of chromosome 21 (Petersen and O’Bryant, 2019; Sosa et al., 2017). Strong evidence from human genetics and transgenic mouse models has indicated the role of APP in the aetiology and pathogenesis of AD, which is commonly characterized by the presence of intracellular tangles of

hyperphosphorylated tau and extracellular plaques (Hardy and Selkoe, 2002; Reitz, 2012; Selkoe, 1999). These plaques are caused by the extracellular deposition of amyloid-b (Ab) peptide, which results from the amyloidogenic cleavage of the APP in the cerebral cortex (reviewed in Haass et al. (2012), Kamenetz et al. (2003), Saura et al. (2004), Selkoe and Hardy (2016) and Yan (2017)). It is well established that Ab oligomers cause neuronal dysfunction and network alterations in learning and memory circuitry prior to clinical onset of AD, leading to cognitive decline. Mutations in APP have been linked to familial cases of AD. The most widely accepted models of disease aetiology propose that Ab aggregates or oligomers trigger a cascade of events causing damage to neuronal connections and cell death (Catalano et al., 2006; Klevanski et al., 2015; Scheuner et al., 1996; Tanzi and Bertram, 2005). The current principal AD therapeutic strategy is to reduce Ab generation or Ab-induced excitotoxicity, however this can potentially interfere with normal cellular processes (Hardy and De Strooper, 2017; Kurz and Perneczky, 2011). Ligand(s) for APP may also affect progression of AD, by modulating either the processing

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or function of APP, which acts as a cell surface receptor or adhesion molecule that is crucial for cell survival (Ho and Su¨dhof, 2004; Huang et al., 2017; Mu¨ller et al., 2017). Therefore, efforts to identify a number of extracellular partners that directly or indirectly interact with APP and modulate its trafficking, surface expression and cleavage may provide potential drug targets for AD therapy. Hence, it is important to unravel the physiological function of APP in order to gain a deeper understanding of its involvement in the pathogenesis of AD and to develop a meaningful therapeutic strategy for the treatment of AD and/or dementia with minimal side-effects.

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Amyloid-like protein (APLP)

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Amyloid-like protein 1 and 2, also known respectively as APLP1 and APLP2, are membrane proteins within the same protein family as APP (Wasco et al., 1993, 1992). They have the same expression pattern as APP and they are able to interact in both cis and trans (Heber et al., 2000; Herms et al., 2004; Soba et al., 2005). They are processed in a similar way although only APP can generate an amyloidogenic fragment owing to sequence divergence at the internal Ab site (Fig. 1A) (Eggert et al., 2004; Schauenburg et al., 2018). They have been shown to coordinate development of the mammalian brain by regulating migration and differentiation of neural stem cells (Korte et al., 2012; Shariati et al., 2013). Knockout mouse models of APLP2 and its homologues, APP and APLP1, have shown a strong indication that APLP2 has the key physiological role among the APP family members (Herms et al., 2004; Truong et al., 2019; Vnencak et al., 2015; Walsh et al., 2007; Weyer et al., 2014; Zhang et al., 2013). APLP2 and APP are known to regulate synaptic plasticity, neurite outgrowth and neural cell migration (Schilling et al., 2017; Schrenk-Siemens et al., 2008; Wang et al., 2009). Since APP plays a key role in the molecular pathology of AD, it connotes that APLP2, despite containing no Ab sequence, may also contribute to the pathogenesis of AD (Midthune et al., 2012). It is still not fully understood what differentiates the APP gene from the closely related APLP1 and APLP2 genes that thus far are not linked to AD.

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Contactin (CNTN) and Contactin-associated proteinlike (CNTNAP) families Contactins (CNTNs) are proteins belonging to a specific subclass of the immunoglobulin CAM superfamily (IgCAM), which as neural cell recognition molecules play important roles in the formation and maintenance of the neuronal system (reviewed in Chatterjee et al. (2019) and Shimoda and Watanabe (2009)). There are six members (CNTN1 to -6); each exerts a specific function. They share similar structural domains with six Nterminal Ig domains, four fibronectin type III (FNIII) domains, and are tethered to the cell membrane with a C-terminal GPI-anchor (Fig. 1B). Contactins interact with members of Contactin-associated protein-like family (CNTNAP) (Burbach and van der Zwaag, 2009; Corfas, 2004; Lu et al., 2016), the extracellular domain of which contains a coagulation factor 5/8 type C (FVIIIC)/discoidin

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domain; laminin, neurexin, sex hormone binding globulin (LNS or L) domains; EGF-like domain (EGF); and a fibrinogen-like (FBG) domain (Fig. 1C). Several genome-wide association studies (GWAS) have successfully identified CNTN genes as risk factors for AD (Table 1). In addition, several members of CNTN proteins have been reported to interact with APP (Bai et al., 2008; Ma et al., 2008a,b; Mattson and van Praag, 2008; Osterfield et al., 2008). However, the physiological importance of these interactions and their involvements in disease pathology are largely unknown. In this review, we provide an overview on the relationship between APP and the CNTN family, and their role in the genetic and pathological manifestation of AD.

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GENETICS SUMMARY

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Increased power in genetics screening and analysis has led to the discovery of common mutations in genes associated with AD. Several major GWAS have discovered genetic links between the CNTN family and dementia, ranging from single nucleotide polymorphisms (SNPs) to large alterations within chromosomes (Table 1). For examples, Blacker et al. conducted a high-resolution genomic screen of 437 AD families (Blacker et al., 2003) and identified a linkage between chromosome 3p26 with AD. Interestingly, the polymorphism marker D3S2387 is only 1.1 Mb from CNTN4 on chromosome 3p26, and is associated with early/mixed AD. In addition, three GWAS also identified SNPs within CNTN1 and CNTN2 that are associated with late onset Alzheimer’s disease (LOAD) (Carrasquillo et al., 2009; Li et al., 2008; Reiman et al., 2007). Furthermore, a meta-analysis for LOAD biomarker genes found 235 and 407 SNPs in CNTN1 and CNTN2, respectively (Medway et al., 2010).

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EXPRESSION ANALYSES IN POST-MORTEM AD BRAIN TISSUE

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Gene expression levels have been analyzed in the brain tissue of subjects with AD and related diseases (Allen et al., 2016). Human CNTN and CNTNAP gene expression was analyzed from the Mayo human-RNAseq database, specifically in the temporal cortex (Table 2 contains summary demographic data). Table 3 highlights significant results, which show upregulation of CNTN1 (isoform 3 only); downregulation of CNTN2 (isoform 2 only); downregulation of CNTN5 gene; upregulation of CNTNAP3 and downregulation of CNTNAP4 (isoform 2 only). It should be noted that there are low donor numbers and some low abundance reads for some isoforms, and that this data should be considered with caution. Whilst no definitive conclusions can currently be drawn, preliminary data shows changes in CNTN and CNTNAP expression in AD patients which warrants further study.

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CONTACTIN FAMILY AND RELATED APP FUNCTION

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CNTN-APP binding and interaction has been mainly studied through in vitro and in vivo models with genetic

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Table 1. A summary of the genetic studies which relate CNTN family mutations with AD and late-onset AD (LOAD) Associated disease

Gene

Chromosomal location

Mutated region

Reference

LOAD

CNTN1

12

LOAD

CNTN2

1

Alzheimer’s disease Alzheimer’s disease Alzheimer’s disease Alzheimer’s disease Alzheimer’s disease LOAD Aging in males

CNTN2

1

rs4951168 rs7523477 rs10900451 rs4950982 N/A

(Medway et al., 2010), and references within (Medway et al., 2010), and references within (Suter et al., 1995)

CNTN3

3

74262568–74521140

(Leidinger et al., 2013)

CNTN4

3

3p26

(Chittoor et al., 2016)

CNTN4 CNTN6 CNTN5

3

D3S2387 (3p26)

(Blacker et al., 2003)

11

rs10501927

(Harold et al., 2009)

CNTNAP2 CNTNAP2

7 7

(Hirano et al., 2015) (Iakoubov et al., 2015)

Aging in females

CNTNAP4

16

rs802571 Insertion 147,704,059–147,707,263 (7q36.1) CNVR6782.1del/del

(Iakoubov et al., 2013)

Table 2. Summary of demographics for donors with and without AD. Data taken from Mayo RNA-seq database and temporal cortex dataset (Allen et al., 2016) Category

Age at death (yrs) APOE

Total Sex

Control

AD

P-value

Mean

SD

Mean

SD

84 12 ApoE23 1 ApoE24 57 ApoE33 8 ApoE34 78 37 F/41 M

10

84 4 ApoE23 35 ApoE33 36 ApoE34 7 ApoE44 82 49 F/33 M

9

9.1E
01

1.2E
01

Table 3. Significant RNA-sequencing values in the temporal cortex of the AD cohort. Arrow indicates up/down regulation in AD cohort compared to control cohort Differentially regulated CNTN gene expression in the temporal cortex of AD cohort

CNTN5

CNTNAP3

Mean SD SEM Mean SD SEM

Control

AD

P-value

8.484 6.32 0.7156 3.232 1.629 0.1845

6.325 3.716 0.4103 4.015 1.466 0.1619

0.0089

Differentially regulated Contactin transcripts in the temporal cortex of AD cohort CNTN1 Mean 66.93 83.91 ENST00000547702 SD 38.34 29.48 SEM 4.341 3.256 CNTN2 Mean 49.17 39.82 ENST00000481872 SD 38.01 15.27 SEM 4.304 1.686 CNTN5 Mean 5.812 4.398 ENST00000524871 SD 4.133 2.357 SEM 0.468 0.2603 CNTNAP4 Mean 10.81 7.805 ENST00000619533 SD 5.816 2.973 SEM 0.6585 0.3284

Regulation ;

0.0017 "

0.002 " 0.041 ; 0.0083 ; <0.0001 ;

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knockout and mutations. APP is a well-studied protein and numerous proteins have been reported to bind to APP (Ho and Su¨dhof, 2004; Hoe et al., 2009a,b; Lourenc¸o et al., 2009; Rice et al., 2012). CNTN family proteins are known to interact with APP and its orthologs in both cultured neurons and the developing brain (Ma et al., 2008a,b; Osterfield et al., 2008; Osterhout et al., 2015). A summary of the reported in vitro interactions between CNTN and CNTNAP with APP/APLP are listed in Table 4.

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CONTACTIN 1 (F3/CONTACTIN)

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Contactin 1 (CNTN1, also known as F3) expression becomes apparent after birth (Shimoda and Watanabe, 2009) and is expressed on migrating small cell body neurons (granule cells) in the postnatal cerebellum. CNTN1 changes in cellular distribution during granule cell migration, as it is downregulated on the granule cell bodies but remains expressed on axonal extensions within the molecular layer (Virgintino et al., 1999). CNTN1 is also expressed in the axons and cell bodies of the Golgi cells and mossy fibers (Faivre-Sarrailh et al., 1992). CNTN1

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has general roles in neuron-glia interactions and formation of the nodes of Ranvier (Ascano et al., 2012; Peles and Salzer, 2000), axon growth and guidance of the olfactory and optical systems, and myelin subdomain organization (Bizzoca et al., 2012; Falk et al., 2002; Mohebiany et al., 2014). Their function is facilitated by interactions with associated molecules such as CNTNAP1 (Peles, 1997). Overexpression of CNTN1 promotes neurogenesis in adult hippocampus, which correlates well with enhanced synaptic plasticity and memory (Puzzo et al., 2013). Interestingly, overexpression of CNTN1 efficiently improve synaptic plasticity and memory in aged mice, in part due to the downregulation of neuronal apoptosis in the hippocampus (Puzzo et al., 2015). CNTN1 was identified as an APP interacting protein using a time-controlled transcardiac perfusion crosslinking method in mouse tissue (Bai et al., 2008). A physical interaction was found between CNTN1 and APP, which resulted from the binding of CNTN1 to the extracellular domain of APP (Bai et al., 2008). Functionally, CNTN1 has been shown to affect APP processing and Ab production in vivo (Gulisano et al., 2017; Puzzo et al., 2015, 2014, 2013). In aged mice, overexpression

Table 4. Summary of the reported in vitro interactions between APP and APLP with CNTN and CNTNAP family members CNTNAPP

Interaction

Modulatory effect

Reference

+/
?

CNTN1 CNTN1

Physical CNTN1/2 overexpression

N/A Increase of the APP non-amyloidogenic pathway

N/A +

CNTN1

Prevents inappropriate migration and outgrowth

CNTN2

MsContactin endogenous ligand of APPL (APP-like) CNTN1/2 and BACE

CNTN2

Functional ligand

CNTN2 CNTN3

Ligand which weakens binding between APP and ligand TGFb2 Binding partners

Enhances AICD production; negatively modulates neurogenesis Inhibits neuronal death

(Bai et al., 2008) (Puzzo et al., 2015, 2014) (Ramaker et al., 2016, 2013) (Gulisano et al., 2017) (Ma et al., 2008a, b) (Tachi et al., 2010)

N/A

CNTN4

Binding partners

Not known

(Osterfield et al., 2008) (Osterfield et al., 2008)

CNTNAPAPP

Interaction

Modulatory effect

Reference

CNTNAP1

Forms a ɣ-secretase associated complex for APP processing

Reduces Ab levels and amyloid plaque formation

(Hur et al., 2012)

+

ContactinAPLP

Interaction

Modulatory effect

Reference

+/
?

CNTN3

APLP1 binding partner

Not known

N/A

CNTN4

APLP1 binding partner

Not known

CNTN5

APLP1 binding partner

Not known but suggested to regulate APLP1 processing during synaptogenesis

(Osterfield et al., 2008) (Osterfield et al., 2008) (Osterfield et al., 2008) (Shimoda et al., 2012)

CNTNAPAPLP

Interaction

Modulatory effect

Reference

CNTNAP1

CNTNAP1 overexpression

Inhibits APP and Ab production

(Fan et al., 2013)

Reduction in sAPPa

Modulates NgCAM-dependent axon outgrowth

+ +
+

N/A

N/A N/A

+

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of CNTN1 shifts the enzymatic processing of APP that favors the production of sAPPa (Puzzo et al., 2015). This positively regulates hippocampal N-methyl-D-aspartate (NMDA) receptor function, synaptic plasticity and spatial memory (Taylor et al., 2008). The exact mechanism of how CNTN1 regulates APP processing is unknown. However, it is plausible that CNTN1, when bound to APP, protects the b-cleavage site from being accessible by bsecretase 1 (BACE1), an essential protease for the generation of Ab peptide and is a major therapeutic target for AD. Invertebrates express a single Contactin ortholog, which has the highest sequence similarity to CNTN1 (Faivre-Sarrailh, 2004; Ganot et al., 2015; Katidou et al., 2013). Studies performed in the hawkmoth, Manduca sexta has identified Manduca Contactin (MsContactin) as an endogenous ligand for APPL during key periods of neuronal migration and axon outgrowth (Ramaker et al., 2016, 2013). Altogether, these findings provide an experimental evidence for the physiological role of CNTN-APP signaling in the proper functioning of the nervous system. It is therefore crucial to investigate how dysregulation of CNTN-APP interactions may contribute to neuronal dysfunction and neurodegeneration such as AD.

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CONTACTIN 2 (TAG-1)

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Contactin 2 (CNTN2, also known as TAG-1) has a similar sequence and structure with CNTN1 (Yoshihara et al., 1995), and therefore, un-surprisingly, shares many similar functions in the developing nervous system (Falk et al., 2002; Kimberly et al., 2001; Salzer et al., 2008; Zuko et al., 2011). CNTN2 expression starts early in development and is regulated in a spatio-temporal pattern in a subpopulation of neurons in the spinal cord, dorsal root ganglia and retinal ganglion cells (Shimoda and Watanabe, 2009). CNTN2 is thought to be a neuronal migration cue since neurons migrate along CNTN2expressing axons of the developing cerebral cortex system (Denaxa et al., 2001; Kyriakopoulou et al., 2002). In the postnatal cerebellum, CNTN2 is transiently expressed on pre-migratory granule cells (Yamamoto et al., 1986). CNTN2 is involved in many physiological neuronal processes, such as the interaction with glial cells (Suter et al., 1995), structural integrity of retinal ganglion cell axons (Chatzopoulou et al., 2008), axonal guidance (Baeriswyl and Stoeckli, 2008; Furley et al., 1990; Wolman et al., 2008) and synapse formation (Leshchyns’ka and Sytnyk, 2016). Consistent with the alteration of synaptic function and axonal loss in pre-symptomatic AD cases (Mattson, 2004), CNTN2 has been widely associated with the disease pathogenesis and is known to interact with AD associated proteins. Using several techniques, from conventional enzyme-linked immunosorbent assay (ELISA) and fluorescence correlation spectroscopy to liquid chromatography–tandem mass spectrometry (LC– MS/MS), there have been a few studies investigating the level of CNTN2 in the cerebrospinal fluid (CSF) of AD patients (Yin et al., 2009) (Chatterjee et al., 2018, 2017). In some studies, a significant decrease in the level

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of CNTN2 in the CSF of AD patients has been reported (Chatterjee et al., 2018, 2017). The reduction of CNTN2 correlates with the levels of phosphorylated tau and the severity of cognitive decline in AD patients (Chatterjee et al., 2018). This demonstrates the viability of the reduced level of CNTN2 in the CSF, which signifies synaptic or axonal loss, as a potential biomarker for AD. Conversely, higher levels of CNTN2 have also been reported in three pooled AD CSF samples (Yin et al., 2009). Interestingly, the levels of CNTN precursor GNA2 are also significantly elevated in AD brain (Huang et al., 2004). An interesting possibility for the apparent increase in the levels of CNTN2 is due to alterations of CNTN2 expression over the course of disease progression, initially increasing in the early disease stages and then reducing with the severity of AD (Yin et al., 2009). Similarly to CNTN1, previous studies have identified CNTN2 as a functional ligand of APP by coimmunostaining and co-immunoprecipitation assays in the mouse brain (Ma et al., 2008a,b; Mattson and van Praag, 2008; Osterfield et al., 2008). CNTN2 is able to influence and enhance the production of APP intracellular C-terminal domain (AICD) in the cytosol with a concomitant dose-dependent increase in Ab peptide production (Konietzko, 2012; Ma et al., 2008a,b). Neural precursor cells from CNTN2, APP or CNTN2;APP double knockout mice exhibit enhanced neurogenesis phenotype, suggesting that CNTN2 and APP functionally interact to modulate neurogenesis. More recently, a conflicting report using both overexpression and endogenous assays has found that CNTN2 has no effect on APP processing (Rice et al., 2013). Despite this, Tachi et al. has found that CNTN2 inhibits neuronal death by weakening binding of APP and ligand TGFb2 which would cause apoptosis. They further found that CNTN2 expression in young mouse hippocampal neurons may predispose neurons to cell death and therefore be prominent in AD progression (Tachi et al., 2010). CNTN2 is a physiological substrate of BACE1 and undergoes BACE1-dependent cleavage both in Chinese Hamster Ovary (CHO) cells and primary neuronal cultures (Gautam et al., 2014; Kuhn et al., 2012; Zhou et al., 2012). Overexpression of BACE1 in CHO cells increases the release of exogenous CNTN2 ectodomain. In contrast, pharmacological inhibition of BACE1 results in a reduction of soluble CNTN2 concomitant with an increase in total CNTN2 level in the cell lysates. BACE1 also regulates endogenous CNTN2 cleavage in mouse primary neurons (Gautam et al., 2014). Importantly, the levels of CNTN2 are reduced in post-mortem AD tissues and are inversely correlated with increased levels of BACE1 activity in the same samples (Gautam et al., 2014). In accordance, there is a more than 1.5-fold reduction in the levels of CNTN2 in the CSF of BACE1 knockout mice when compared with those in the wild-type littermates (Dislich et al., 2015). BACE1 undergoes a post-translational sugar modification via the addition of bisecting Nacetylglucosamine (GlcNAc), which is highly abundant in the brain (Kizuka et al., 2015). The lack of this modification leads to aberrant shunting of BACE1 to the late endo-

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somes and an accelerated lysosomal degradation, which in turn results in a decrease in Ab production. However, other BACE1 substrates including CNTN2 are normally cleaved in GnT-III deficient mice, which have impairment in the GlcNAc biosynthetic pathway. This is likely due to the effect of bisecting GIcNAc on BACE1 being specific to APP (Kizuka et al., 2015). Interestingly, BACE1 knockout mice exhibit a significant increase in the expression of surface CNTN2 due to impaired cleavage (Kizuka et al., 2015). These data demonstrate that although APP and CNTN2 are both substrates of BACE1, their cleavages can be differentially modulated by BACE1 modification by GlcNAc.

384

CONTACTIN 3 (PANG/BIG-1)

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Contactin 3 (CNTN3) is the least characterized member of the Contactin protein family. CNTN3 is mainly expressed in the adult brain in cell types such as granule cells of the hippocampus dentate gyrus and neurons in the superficial layers of the cerebral cortex (Shimoda and Watanabe, 2009; Yoshihara et al., 1995). It has been shown to have involvement in neuritogenesis and axiogenesis, and can promote neurite outgrowth (Connelly et al., 1994; Yoshihara et al., 1995, 1994). To the best of our knowledge, CNTN3 has not been formally associated with AD, however, some studies have suggested potential links, including the known interaction between CNTN3 and APP (Osterfield et al., 2008). Gene microarray data analysis revealed that the expression of CNTN3, as well as CNTN1 and 4, was downregulated in carotid atheromatous plaque compared with intact tissues collected from the same patients (Zeng et al., 2015). The formation of plaque is considered as a risk factor for ischemic stroke and such neurovascular dysfunction is known to be frequently observed in AD patients (Nelson et al., 2016; Yarchoan et al., 2012) In addition, CNTN2, CNTN3 and CNTNAP2 were predicted to be target genes of differentially expressed miRNAs between AD patients and healthy controls (Leidinger et al., 2013). From structural analysis, the protein tyrosine phosphatase receptor type G (PTPRG) was found to interact with CNTN3, 4, 5 and 6 while PTPR zeta (PTPRZ) binds only to CNTN1 (Bouyain and Watkins, 2010). Although little is known about the role and function of PTPRG, one study shows that activated astrocytes surrounding amyloid plaques expressed high levels of PTPRG in AD mouse model (Lorenzetto et al., 2014). Due to overall lack of research into its molecular function, it remains unclear whether CNTN3 can contribute to AD pathogenesis.

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CONTACTIN 4 (BIG-2)

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CNTN4 is an extensively studied protein within the Contactin family that has been implicated in various neurodevelopmental disorders (reviewed in (OguroAndo et al., 2017)). CNTN4 gene is located on chromosome 3p26.2-p26.3, the disruption or deletion of which are strongly associated with autism spectrum disorder (ASD), (Bakkaloglu et al., 2008; Cottrell et al., 2011; Dijkhuizen et al., 2006; Fernandez et al., 2004; Glessner et al., 2009; Roohi et al., 2008). CNTN4 is

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mainly expressed in the olfactory bulb, thalamus and cortical pyramidal and interneurons (Yoshihara et al., 1995). CNTN4 is detectable during embryonic development and into adulthood within the axons of olfactory sensory neurons. Functionally, CNTN4 acts as one of the axon guidance molecules crucial for the proper formation and development of the olfactory and optic systems (Fernandez et al., 2004; Kaneko-Goto et al., 2008; Osterhout et al., 2015). Aside from the genetic studies in Table 1, there are currently limited studies that show a link between CNTN4 and AD. However, there are several reports of functional protein interaction between CNTN4 and APP. Osterfield et al. have previously found CNTN4 as one of the major binding partners for APP and APLP1 in embryonic chick neurons (Osterfield et al., 2008). Among those binding partners, which include CNTN3 and NgCAM, CNTN4 shows the highest binding affinity towards APP and APLP1. Only the FNIII domains of CNTN are required for binding to the ectodomain of APP, which leaves the Ig domains of CNTN4 free to interact with other binding partners. A study by Huberman et al. later demonstrated a functional importance of CNTN4 and APP interaction in promoting target-specific axon arborization in the retina (Osterhout et al., 2015). Co-expression of CNTN4 or NgCAM with APP in transfected cells demonstrated expression of full-length APP and subsequently an increase of APP processing fragment CTFa, demonstrating a modulatory role of CNTN4 on APP processing (Osterfield et al., 2008). Despite this, the influence of CNTN4 in Ab production remains to be established. Research has shown reduced serum uric acid (SUA) levels are associated with neurological disorders such as AD (Du et al., 2016; Spitsin and Koprowski, 2010). SUA is a known biomarker for neurodegenerative disorders such as AD and vascular dementia (Mousavi et al., 2014). Previous studies have found genetic links between SUA concentrations and SNPs in CNTN4 gene (Cargile et al., 2002; Voruganti et al., 2009). Further studies confirmed a strong association between lower levels of SUA concentrations and genetic variants within the 3p26 region, including CNTN4 (Chittoor et al., 2016; Du et al., 2016).

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CONTACTIN 5 (NB-2)

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Contactin 5 (CNTN5) function was first studied through CNTN5 deficient mice. It was demonstrated that neural excitability in the midbrain nucleus of the auditory pathway was attenuated in CNTN5 deficient mice (Li et al., 2003). In line with this report, CNTN5 deficient mice exhibited increased cell death and altered responses to stimuli in auditory pathways (Li et al., 2003; Toyoshima et al., 2009). CNTN5 is expressed transiently during first postnatal week in glutamatergic neurons of the central auditory system in rat. Expressions reached peak levels at postnatal day 3 in the cerebellum and declined thereafter (Ogawa et al., 2001). Although the expression of CNTN5 has yet to be systematically analyzed, CNTN5 is reported to be expressed in layers II-V and in the cingu-

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lum of the brain (Kleijer et al., 2015; Ogawa et al., 2001; Toyoshima et al., 2009). As for the detailed molecular function of CNTN5, Ogawa et al., 2001 reported that the neurite outgrowth of primary cultures of rat cortical neurons was promoted on CNTN5-coated culture plates (Ogawa et al., 2001). In addition, CNTN5 has also been implicated in the regulation of the directionality of some neurons and the organization of axo-axonic connections (Ashrafi et al., 2014). The link between CNTN5 and AD comes from a GWAS that identifies a SNP in the intronic region of CNTN5 gene (Harold et al., 2009). However, the expression of CNTN5 protein is not significantly different in postmortem brains samples of sporadic AD and controls, and does not correlate with the levels of Ab, soluble Ab or insoluble Ab (Whitehouse et al., 2013). It is interesting to note that CNTN5 can form a cis-complex with APLP1 on the presynaptic membrane of cultured hippocampal neurons (Osterfield et al., 2008; Shimoda et al., 2012). Shimoda et al. has investigated the role of CNTN5 in synapse formation, and previously a CNTN5 deficiency in mouse caused a significant reduction in the number of synapses (Toyoshima et al., 2009). Given that the functional role of their interaction is unknown, it is therefore unclear how CNTN5 may contribute to the development of AD.

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CONTACTIN 6 (NB-3)

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CNTN6 is located next to CNTN4 on chromosome 3p26 and is expressed in pyramidal neurons of layers II, III and V in the cortex (Lee et al., 2000; Sakurai et al., 2010; Takeda et al., 2003; Zuko et al., 2016). The expression of CNTN6 is restricted to neurons and is mainly upregulated during early postnatal stage in mice (Cui et al., 2004). Expression in the cerebellum increases before a dramatic decrease occurs at P7 (Lee et al., 2000; Takeda et al., 2003). Protein expression reached the maximum level at P15 before declining to a constant level in adulthood (Sakurai et al., 2009). CNTN6 is therefore thought to have a role in postnatal cerebellar development. As predicted from its chromosomal location, CNTN6 has been associated with ASD and other psychiatric disorders (Hu et al., 2015; Oguro-Ando et al., 2017; Zuko et al., 2011). While the direct interaction between APP and CNTN6 was not detected (Osterfield et al., 2008), GWAS provides a suggestive linkage between AD and CNTN6, as well as CNTN4 and CHL1 (Blacker et al., 2003). The functional role of CNTN6 has been studied through CNTN6 deficient mice. Takeda et al., 2003 reported the motor coordination defected without altered muscle strength in CNTN6 knockout mice (Takeda et al., 2003). Subsequently, it was demonstrated that apical dendritic orientation of visual cortical pyramidal neurons was altered in the CNTN6 deficient mice (Ye et al., 2008). To note, morphological changes of apical dendrites have been reported in vivo with APP overexpression and APP deficiency (Alpa´r et al., 2006; Tyan et al., 2012). In addition to the role on the morphological properties, CNTN6 is suggested to have functions on the synap-

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tic activity via interaction with VGLUT1 and 2, which mediate the uptake of glutamate into presynaptic vesicles of glutamatergic neurons. It was demonstrated that the density of VGLUT1 and 2 was reduced in CNTN6 deficient mice (Sakurai et al., 2010), resembling the loss of VGLUT1 and 2 in both AD patients and Ab-based AD model mice, respectively (Canas et al., 2014; Kashani et al., 2008; Rodriguez-Perdigon et al., 2016). While the exact molecular function of CNTN6 on AD remains unclear, CNTN6 may contribute to AD pathogenesis via effects on dendrite morphology and synaptic activity properties.

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CONTACTIN-ASSOCIATED PROTEIN-LIKE (CNTNAP) FAMILY

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The Contactin-associated protein-like (CNTNAP) family is important to be considered because recent studies have implicated these genes and CNTNAP protein aggregation in the aetiology of neurodevelopmental disorders and neurodegenerative diseases such as ASD and AD (Hur et al., 2012; Poot, 2015; Ross and Poirier, 2004). There are five members in the Contactinassociated protein (CNTNAP1-5) family, all of which are transmembrane proteins with similar structures, albeit exhibiting functional specificity (Bralten et al., 2010; Spiegel et al., 2002; Weichenhan et al., 2008). CNTNAP proteins have roles in nerve excitation and conduction, neurotransmitter release in forming myelinated axons and in maintaining the stability of adjacent connections (Gokce and Sudhof, 2013; Zou et al., 2017). CNTNAP proteins are expressed in various regions of the brain and have potential roles in regulating cell–cell interaction and cell recognition in neural networks. For example, CNTNAP3 is expressed in Purkinje cells in the cerebellum and CNTNAP4 is expressed in neural progenitor cells in the subventricular zone (Spiegel et al., 2002; Yin et al., 2015). To our best knowledge, there are no links between the CNTNAP protein family and AD, although two studies linked to aging are reported by Iakoubov et al. which discovered copy number variants in the CNTNAP2 and CNTNAP4 genes, respectively (Table 1) (Iakoubov et al., 2015, 2013). CNTNAP3-5 proteins are not as well-studied as CNTNAP1-2, and their functions are not well characterized. Here we focus on two well-studied members of the CNTNAP family; CNTNAP1 and CNTNAP2.

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CONTACTIN-ASSOCIATED PROTEIN-LIKE 1 (CNTNAP1)

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CNTNAP1 is encoded by the CNTNAP1 gene that is located on chromosome 17q21. CNTNAP1 is a 190-kDa neuronal transmembrane protein and is highly concentrated at the paranodal junctions of the peripheral and central nervous systems (Peles et al., 1997; Zou et al., 2017). Structurally, CNTNAP has a large extracellular domain which associates with CNTN, and a short intracellular domain (Fig. 1C) (Peles et al., 1997; Yoshihara et al., 1995). CNTNAP forms a complex with CNTN and Neurofascin 155 (NF-155) in order to act as a barrier between the nodes of Ranvier and internodes, and is

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involved in the propagation of action potentials and mediation of signal transport (Gollan et al., 2003; Poliak et al., 2003; Sherman et al., 2005; Ullrich et al., 1995). CNTNAP also mediates the formation, differentiation and outgrowth of neurons and astrocytes (Wu et al., 2016). Interestingly, CNTNAP1 also interacts with the AMPA-type glutamate receptors and regulates their trafficking to synapses (Santos et al., 2012). Normally APP is cleaved by a-secretase and csecretase, however in AD pathological cases it is differentially cleaved by b-secretase and c-secretase, which in turn generates Ab peptides. CNTNAP1 has been shown to interact with APP and form a complex with c-secretase, suggestive of its involvement in the pathology of AD (Fan et al., 2013; Hur et al., 2012; Zou et al., 2017). Indeed, CNTNAP1 is upregulated and distributed in a clustering pattern around amyloid plaques in the cerebral cortex of APP/PS1 mice (Fan et al., 2013). Despite this, the role of CNTNAP1 in APP processing remains controversial. In one study, siRNA-mediated knockdown of CNTNAP1 in HEK293 cells stably expressing wild-type APP was able to reduce Ab production (Hur et al., 2012). However, in another study using HEK cells that stably expressing the Indiana mutant of APP (V717F), overexpression of CNTNAP1 was reported to downregulate the expression of APP and subsequent generation of Ab (Fan et al., 2013). This discrepancy likely arises due to the use of two different APPs, of which cleavages by c-secretase are known to be affected by mutations within APP itself (De Jonghe et al., 2001). The exact role and mechanism by which CNTNAP1 affects APP stability and/or proteolytic cleavage requires further investigation.

CONTACTIN-ASSOCIATED PROTEIN-LIKE 2 (CNTNAP2) CNTNAP2, a neurexin-related cell adhesion molecule, is encoded by the CNTNAP2 gene. The gene is located at chromosome 7q35-q36 and is one of the largest genes in the human genome, spanning over 2.3 Mb of genomic sequence. CNTNAP2 shares 45% amino acid identity to CNTNAP1 and exhibits many structural similarities (Fig. 1C). While CNTNAP1 is present at paranodal junctions, CNTNAP2 is expressed in juxtaparanodes and some isolated paranodal loops (Poliak et al., 2001, 1999). CNTNAP2 forms a heterodimeric complex with CNTN2, which acts as a scaffold to cluster K+ channels at the juxtaparanodal region (Poliak et al., 2003; Traka et al., 2003). Little is understood about the cellular and molecular mechanisms whereby CNTNAP2 controls brain function. CNTNAP2 stabilizes resting potential by forming a cluster of K+ channels in myelinated axons and neuralglia interactions (Horresh et al., 2008; Lancaster et al., 2011; Poliak et al., 2001, 1999). Previous reports show that sequence variation in CNTNAP2 is associated with altered functional connectivity in the human frontal lobe (Scott-Van Zeeland et al., 2010). Further, CNTN2 deficient mice show reduced CNTNAP2 expression levels suggesting the disrupted CNTNAP2 expression is associ-

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ated with cognitive abnormalities as observed in these mice (Savvaki et al., 2008). CNTNAP2 has been shown to be involved in several human diseases beyond the scope of this review (SaintMartin et al., 2018). There are few reports associating CNTNAP with AD. CNTNAP2 gene and protein expression is shown to be directly downregulated by STOX1A. STOX1A gene expression has been shown to be upregulated and associated with LOAD pathology (van Dijk et al., 2010). Consequently, CNTNAP2 mRNA levels in the hippocampus of AD patients were significantly decreased in the LOAD patient samples compared to non-demented controls. (Van Abel et al., 2012). Finally, CNTNAP2 is shown to play a role beyond disease, in the localization of voltage-gated potassium channel (VGKC). Patients with neurological autoimmune encephalopathies, 35% of who are commonly diagnosed with a neurodegenerative disorder, have antibodies directed against the VGKC complex in serum (Flanagan et al., 2010; Gresa-Arribas et al., 2016; McKeon, 2016). Some of the target proteins are physically coupled to potassium channels (LgI1 and CNTNAP2). However, in more than 50% of VGKC complex antibody-positive cases, the LgI1 and CNTNAP2 antibodies are not detected (Klein et al., 2013).

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WORKING HYPOTHESIS MODEL FOR INTERACTION BETWEEN CONTACTIN FAMILY AND APP

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This review initially summarized the genetic links between CNTN, CNTNAP and AD. GWAS has identified specific genetic links and associations between the CNTN family and dementia. These range from SNPs to large alterations in the chromosomes, and have been mainly found in CNTN1, 2 and 4. The Mayo human-RNAseq database has allowed gene expression levels in brain tissue of subjects with AD to be investigated. Current results suggest that there is altered expression of human CNTN and CNTNAP in AD patients. This has justified further investigation into the link between CNTN and CNTNAP, and their roles in AD. Initially we have sought to define the roles of CNTN and CNTNAP in regulating APP function. Many of the described functions between the CNTN family and APP interaction fall within the three broad categories of our model hypotheses (Fig. 2). We hypothesize that when these functions are disrupted or imbalanced, this leads to aberrant APP processing and pathogenesis of AD. Given the reported changes in CNTN and/or CNTNAP expression in post-mortem AD tissues or CSF from AD patients, we hypothesize that APP processing is altered by an imbalance in the CNTN-APP interaction (Fig. 2). Both the loss and gain of CNTNs can affect APP processing through the non-amyloidogenic and amyloidogenic pathways. Crucially, changes to the amyloidogenic pathway can result in increased levels of Ab, which lead to plaque formation synonymous with AD. CNTN1, 2 and CNTNAP1 are the main contributors to APP processing alterations. Overexpression of CNTN1 and 2 leads to sAPPa increases in the non-

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neurons. For example, insect ortholog APPL directly binds the heterotrimeric G-protein Goa, and APPL ligand MsContactin helps to activate the pathway. APPL-Goa signaling promotes Ca2+dependent retraction responses to local guidance cues encountered by migratory neurons. (Ramaker et al., 2016, 2013; Swanson et al., 2005). It is conceivable that a) CNTN interaction with APP can physically facilitate or inhibit the access of secretases during APP cleavages, b) CNTN sequesters APP binding partners that are controlling the proteolytic cleavage of APP, and c) CNTN alters the intracellular signaling which determines the stability and trafficking of APP on the cell surface. These mechanisms may play roles in controlling neuronal survival versus apoptosis in the pathogenesis of AD. Secondly, we propose roles of dysregulated CNTN and CNTNAP signaling in altering synaptic function, especially synaptic plasticity and excitation/inhibitory (E/I) balance of neuronal circuits (Fig. 2). It is well known that APP plays a central role at the synapse (Hoe et al., 2009a,b; Hoe et al., 2012; Rice et al., 2019) and high levels of its cleavage product Ab reduce glutamatergic synaptic transmission and cause synaptic loss (Hsia et al., 1999; Kamenetz et al., 2003; Mucke et al., 2000; Palop and Mucke, 2010; Walsh et al., 2002). APP interacting proteins are also important for regulation of synaptic function; for example, Rice et al. show sAPP to be ligand specific to synaptic Fig. 2. Potential consequences of disrupted Contactin and APP interaction. It is hypothesized that receptor GABABR1a, and subsechanges in imbalances within the Contactin-APP interaction leads to Alzheimer’s disease pathology. quently modulate synaptic transThis can take place through three proposed routes: (1) APP processing; alterations to (2) synaptic mission and plasticity (Rice et al., plasticity and (3) neuronal integrity. 2019). Synaptic loss induces neuronal dysfunction and pathological hallmarks of AD (DeKosky and amyloidogenic pathway, and consequently decreases in Scheff, 1990; Terry et al., 1991). Pre- and post-synaptic sAPPb and Ab levels (Gulisano et al., 2017; Puzzo membrane interaction and alignment are required to et al., 2015). However, CNTN2, as a functional ligand to mediate synaptic transmission and stabilize synapses APP, has also been shown to cause an increase in AICD, during plasticity events. Emerging evidence has shed which is within the amyloidogenic pathway (Ma et al., lights to the important contribution of the CNTN family in 2008a,b). There are two reports of CNTNAP1 inhibiting maintaining dendritic spine density or synapse number Ab in the amyloidogenic pathway through the ɣin the brain. Several studies have shown the requirement secretase pathway and overexpression, respectively of a proper CNTN1 function in synaptic plasticity (Fan et al., 2013; Hur et al., 2012). Other functional (Gulisano et al., 2017; Milanese et al., 2008; Murai ligands of APP can also interact with a variety of signaling et al., 2002). Puzzo et al. also confirmed that CNTN1 molecules which influence migration and outgrowth of

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affects synaptic plasticity and memory through its effect on adult neurogenesis (Deng et al., 2010; Puzzo et al., 2013). AMPA receptors are the principal glutamate receptors that mediate fast excitatory synaptic transmission in the mammalian brain. Dysregulation of AMPA receptor trafficking often leads to defective synaptic plasticity, E/I imbalance and abnormal network activity. There is a tight control of AMPA receptor numbers at the synapses, which otherwise leads to impaired synaptic plasticity and deficits in learning and memory (Anggono and Huganir, 2012; Guntupalli et al., 2016; Henley and Wilkinson, 2016). The association between CNTNAP1 and subunits of the AMPA receptors has been reported (Santos et al., 2012). This interaction is crucial to promote the forward trafficking of AMPA receptors, and is therefore crucial for excitatory synaptic transmission in the mammalian central nervous system (Santos et al., 2012). Furthermore, the CNTN1 and APP interaction can influence changes in Ca2+ signaling (Dityatev et al., 2008; Parra-Damas and Saura, 2019), long-term depression (Murai et al., 2002), E/I imbalance (Jurgensen and Castillo, 2015) and homeostatic plasticity (Fernandes et al., 2019). Homeostatic synaptic scaling maintains the stability of neural circuits, disruption of which has been widely hypothesized to drive early AD disease progression (Frere and Slutsky, 2018; Gilbert et al., 2016; Pratt et al., 2011; Styr and Slutsky, 2018). For example, there is recent evidence demonstrating that CNTNAP2 is involved in the trafficking of AMPA receptors in pyramidal cells, ultimately inducing morphological changes of dendritic spines and during homeostatic synaptic scaling (Anderson et al., 2012; Fernandes et al., 2019; Varea et al., 2015). Similar studies also suggest that complex CNTNAP2 mutations may disrupt interneurons through dysregulation of AMPA receptor function (Gao et al., 2019). Finally, we posit that alteration in CNTN-APP interaction may negatively impact neuronal integrity, leading to neurodegeneration (Fig. 2). The expression of CNTNs and APP family proteins undergo complex changes over the course of development and aging. CNTN expression tends to occur early in development and either maintains constant expression or decrease after reaching peak expression. These expression patterns show localization in brain areas and cell types. Aberrant expression has been associated with neurodevelopmental disorders such as ASD (Zuko et al., 2011). However, expression analyses revealed up- and down-regulated expression of CNTN and CNTNAP in post-mortem AD brain tissue. Therefore, CNTN not only plays a role in neurodevelopment but also neurodegeneration. Both CNTN and APP are associated with similar developmental and aging functions, such as axonal guidance and degeneration (Mohebiany et al., 2014; Saifetiarova et al., 2017), neurite branching (Huang et al., 2012) and synaptic formation (Priller et al., 2006; Wang et al., 2009). Overall, evidence suggests that there is an important role for APP and CNTN in neurodevelopment and neurodegeneration. Therefore, if there is a functional imbalance or dysregulation of

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CNTN-APP interaction pathways then it is likely that this can lead to neurological disorders, including AD. Most members of the CNTN family of proteins are known to interact with APP. Evidence from GWAS, biochemical and animal studies have suggested a potential involvement of the aberrant CNTN-APP interaction in the pathogenesis of AD. However, the detailed mechanism of actions that underpin this process remain elusive. We hypothesize that alterations in the expression of CNTN and/or CNTNAP negatively affect the proteolytic processing of APP, synaptic activity and neuronal function, leading to the disease manifestation including impairment in synaptic plasticity, cognitive decline and ultimately neurodegeneration. Given the importance of CNTN-APP interaction in normal brain function, it is imperative to further investigate their roles at the cellular levels in order to develop novel therapeutic strategies for the treatment of AD.

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ACKNOWLEDGMENTS

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This review was supported by a QUEX Institute Initiator Grant (to A.O-A and V.A), Alzheimer’s Research UK South West Pump Priming Grants (to A.O-A), Northcott Devon Medical Foundation Grants (to R.A.B and A. OA), a Churchill Fellowship (to R.A.B) and the Clem Jones Centre for Ageing Dementia Research (to V.A). J. W is an Australian Research Council DECRA Fellow (DE170100112).

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DECLARATION OF COMPETING INTEREST

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The authors declare no conflicts of interest.

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REFERENCES

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Allen M, Carrasquillo MM, Funk C, Heavner BD, Zou F, Younkin CS, Burgess JD, Chai H-S, Crook J, Eddy JA, Li H, Logsdon B, Peters MA, Dang KK, Wang X, Serie D, Wang C, Nguyen T, Lincoln S, Malphrus K, Bisceglio G, Li M, Golde TE, Mangravite LM, Asmann Y, Price ND, Petersen RC, Graff-Radford NR, Dickson DW, Younkin SG, Ertekin-Taner N (2016) Human whole genome genotype and transcriptome data for Alzheimer’s and other neurodegenerative diseases. Sci Data 3. https://doi.org/10.1038/ sdata.2016.89 160089. Alpa´r A, Ueberham U, Bru¨ckner MK, Seeger G, Arendt T, Ga¨rtner U (2006) Different dendrite and dendritic spine alterations in basal and apical arbors in mutant human amyloid precursor protein transgenic mice. Brain Res 1099:189–198. https://doi.org/ 10.1016/j.brainres.2006.04.109. Anderson GR, Galfin T, Xu W, Aoto J, Malenka RC, Sudhof TC (2012) Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and spine development. Proc Natl Acad Sci USA 109:18120–18125. https://doi.org/10.1073/pnas.1216398109. Anggono V, Huganir RL (2012) Regulation of AMPA receptor trafficking and synaptic plasticity. Curr Opin Neurobiol 22:461–469. https://doi.org/10.1016/j.conb.2011.12.006. Ascano M, Bodmer D, Kuruvilla R (2012) Endocytic trafficking of neurotrophins in neural development. Trends Cell Biol 22:266–273. https://doi.org/10.1016/j.tcb.2012.02.005. Ashrafi S, Betley JN, Comer JD, Brenner-Morton S, Bar V, Shimoda Y, Watanabe K, Peles E, Jessell TM, Kaltschmidt JA (2014) Neuronal Ig/caspr recognition promotes the formation of

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axoaxonic synapses in mouse spinal cord. Neuron 81:120–129. https://doi.org/10.1016/j.neuron.2013.10.060. Baeriswyl T, Stoeckli ET (2008) Axonin-1/TAG-1 is required for pathfinding of granule cell axons in the developing cerebellum. Neural Dev 3:7. https://doi.org/10.1186/1749-8104-3-7. Bai Y, Markham K, Chen F, Weerasekera R, Watts J, Horne P, Wakutani Y, Bagshaw R, Mathews PM, Fraser PE, Westaway D, St. George-Hyslop P, Schmitt-Ulms G (2008) The in vivo brain interactome of the amyloid precursor protein. Mol Cell Proteomics 7:15–34. https://doi.org/10.1074/mcp. Bakkaloglu B, O’Roak BJ, Louvi A, Gupta AR, Abelson JF, Morgan TM, Chawarska K, Klin A, Ercan-Sencicek AG, Stillman AA, Tanriover G, Abrahams BS, Duvall JA, Robbins EM, Geschwind DH, Biederer T, Gunel M, Lifton RP, State MW (2008) Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. Am J Hum Genet 82:165–173. https://doi.org/10.1016/j.ajhg.2007.09.017. Bizzoca A, Corsi P, Polizzi A, Pinto MF, Xenaki D, Furley AJW, Gennarini G (2012) F3/Contactin acts as a modulator of neurogenesis during cerebral cortex development. Dev Biol 365:133–151. https://doi.org/10.1016/j.ydbio.2012.02.011. Blacker D, Bertram L, Saunders AJ, Moscarillo TJ, Albert MS, Wiener H, Perry RT, Collins JS, Harrell LE, Go RCP, Mahoney A, Beaty T, Fallin MD, Avramopoulos D, Chase GA, Folstein MF, McInnis MG, Bassett SS, Doheny KJ, Pugh EW, Tanzi RE (2003) Results of a high-resolution genome screen of 437 Alzheimer’s Disease families. Hum Mol Genet 12:23–32. https://doi.org/10.1093/hmg/ ddg007. Bouyain S, Watkins DJ (2010) The protein tyrosine phosphatases PTPRZ and PTPRG bind to distinct members of the contactin family of neural recognition molecules. Proc Natl Acad Sci USA 107:2443–2448. https://doi.org/10.1073/pnas.0911235107. Bralten LBC, Gravendeel AM, Kloosterhof NK, Sacchetti A, Vrijenhoek T, Veltman JA, van den Bent MJ, Kros JM, Hoogenraad CC, Sillevis Smitt PAE, French PJ (2010) The CASPR2 cell adhesion molecule functions as a tumor suppressor gene in glioma. Oncogene 29:6138–6148. https://doi.org/ 10.1038/onc.2010.342. Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM (2007) Forecasting the global burden of Alzheimer’s disease. Alzheimer’s Dement 3:186–191. https://doi.org/10.1016/ j.jalz.2007.04.381. Burbach JPH, van der Zwaag B (2009) Contact in the genetics of autism and schizophrenia. Trends Neurosci 32:69–72. https://doi. org/10.1016/j.tins.2008.11.002. Canas PM, Simo˜es AP, Rodrigues RJ, Cunha RA (2014) Predominant loss of glutamatergic terminal markers in a bamyloid peptide model of Alzheimer’s disease. Neuropharmacology 76:51–56. https://doi.org/10.1016/j. neuropharm.2013.08.026. Cargile CB, Goh DL-M, Goodman BK, Chen X-N, Korenberg JR, Semenza GL, Thomas GH (2002) Molecular cytogenetic characterization of a subtle interstitial del(3)(p25.3p26.2) in a patient with deletion 3p syndrome. Am J Med Genet 109:133–138. https://doi.org/10.1002/ajmg.10323. Carrasquillo MM, Zou F, Pankratz VS, Wilcox SL, Ma L, Walker LP, Younkin SG, Younkin CS, Younkin LH, Bisceglio GD, ErtekinTaner N, Crook JE, Dickson DW, Petersen RC, Graff-Radford NR, Younkin SG (2009) Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer’s disease. Nat Genet 41:192–198. https://doi.org/10.1038/ng.305. Catalano SM, Dodson EC, Henze DA, Joyce JG, Krafft GA, Kinney GG (2006) The role of amyloid-beta derived diffusible ligands (ADDLs) in Alzheimer’s disease. Curr Top Med Chem 6:597–608. Chatterjee M, Del Campo M, Morrema THJ, De Waal M, Van Der Flier WM, Hoozemans JJM, Teunissen CE (2018) Contactin-2, a synaptic and axonal protein, is reduced in cerebrospinal fluid and brain tissue in Alzheimer’s disease. Alzheimer’s Res Ther 10:1–11. https://doi.org/10.1186/s13195-018-0383-x. Chatterjee M, No¨ding B, Willemse EAJ, Koel-Simmelink MJA, van der Flier WM, Schild D, Teunissen CE (2017) Detection of contactin-2

in cerebrospinal fluid (CSF) of patients with Alzheimer’s disease using Fluorescence Correlation Spectroscopy (FCS). Clin Biochem 50:1061–1066. https://doi.org/10.1016/ j.clinbiochem.2017.08.017. Chatterjee M, Schild D, Teunissen C (2019) Contactins in the central nervous system: role in health and disease. Neural Regen Res 14:206. https://doi.org/10.4103/1673-5374.244776. Chatzopoulou E, Miguez A, Savvaki M, Levasseur G, Muzerelle A, Muriel M-P, Goureau O, Watanabe K, Goutebroze L, Gaspar P, Zalc B, Karagogeos D, Thomas J-L (2008) Structural requirement of TAG-1 for retinal ganglion cell axons and myelin in the mouse optic nerve. J Neurosci 28:7624–7636. https://doi.org/10.1523/ JNEUROSCI.1103-08.2008. Chittoor G, Kent JW, Almeida M, Puppala S, Farook VS, Cole SA, Haack K, Go¨ring HHH, MacCluer JW, Curran JE, Carless MA, Johnson MP, Moses EK, Almasy L, Mahaney MC, Lehman DM, Duggirala R, Comuzzie AG, Blangero J, Voruganti VS (2016) GWAS and transcriptional analysis prioritize ITPR1 and CNTN4 for a serum uric acid 3p26 QTL in Mexican Americans. BMC Genomics 17:1–8. https://doi.org/10.1186/s12864-016-2594-5. Connelly MA, Grady RC, Mushinski JF, Marcu KB (1994) PANG, a gene encoding a neuronal glycoprotein, is ectopically activated by intracisternal A-type particle long terminal repeats in murine plasmacytomas. Proc Natl Acad Sci USA 91:1337–1341. https:// doi.org/10.1073/pnas.91.4.1337. Corfas G (2004) Mechanisms and roles of axon-Schwann cell interactions. J Neurosci 24:9250–9260. https://doi.org/10.1523/ JNEUROSCI.3649-04.2004. Cottrell CE, Bir N, Varga E, Alvarez CE, Bouyain S, Zernzach R, Thrush DL, Evans J, Trimarchi M, Butter EM, Cunningham D, Gastier-Foster JM, McBride KL, Herman GE (2011) Contactin 4 as an autism susceptibility locus. Autism Res 4:189–199. https:// doi.org/10.1002/aur.184. Cui X-Y, Hu Q-D, Tekaya M, Shimoda Y, Ang B-T, Nie D-Y, Sun L, Hu W-P, Karsak M, Duka T, Takeda Y, Ou L-Y, Dawe GS, Yu FG, Ahmed S, Jin L-H, Schachner M, Watanabe K, Arsenijevic Y, Xiao Z-C (2004) NB-3/Notch1 pathway via Deltex1 promotes neural progenitor cell differentiation into oligodendrocytes. J Biol Chem 279:25858–25865. https://doi.org/10.1074/jbc. M313505200. De Jonghe C, Esselens C, Kumar-Singh S, Craessaerts K, Serneels S, Checler F, Annaert W, Van Broeckhoven C, De Strooper B (2001) Pathogenic APP mutations near the gamma-secretase cleavage site differentially affect Abeta secretion and APP Cterminal fragment stability. Hum Mol Genet 10:1665–1671. DeKosky ST, Scheff SW (1990) Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 27:457–464. https://doi.org/10.1002/ ana.410270502. Denaxa M, Chan CH, Schachner M, Parnavelas JG, Karagogeos D (2001) The adhesion molecule TAG-1 mediates the migration of cortical interneurons from the ganglionic eminence along the corticofugal fiber system. Development 128:4635–4644. Deng W, Aimone JB, Gage FH (2010) New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat Rev Neurosci 11:339–350. https:// doi.org/10.1038/nrn2822. Denisenko-Nehrbass N, Oguievetskaia K, Goutebroze L, Galvez T, Yamakawa H, Ohara O, Carnaud M, Girault JA (2003) Protein 4.1B associates with both Caspr/paranodin and Caspr2 at paranodes and juxtaparanodes of myelinated fibres. Eur J Neurosci 17:411–416. https://doi.org/10.1046/j.14609568.2003.02441.x. Dijkhuizen T, van Essen T, van der Vlies P, Verheij JBGM, SikkemaRaddatz B, van der Veen AY, Gerssen-Schoorl KBJ, Buys CHCM, Kok K (2006) FISH and array-CGH analysis of a complex chromosome 3 aberration suggests that loss ofCNTN4 andCRBN contributes to mental retardation in 3pter deletions. Am J Med Genet Part A 140A:2482–2487. https://doi.org/10.1002/ ajmg.a.31487.

Please cite this article in press as: Bamford RA et al. The Interaction Between Contactin and Amyloid Precursor Protein and Its Role in Alzheimer’s Disease. Neuroscience (2019), https://doi.org/10.1016/j. neuroscience.2019.10.006

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R. A. Bamford et al. / Neuroscience xxx (2019) xxx–xxx 1056 1057 1058 1059 1060 1061 1062 1063 1064 1065 1066 1067 1068 1069 1070 1071 1072 1073 1074 1075 1076 1077 1078 1079 1080 1081 1082 1083 1084 1085 1086 1087 1088 1089 1090 1091 1092 1093 1094 1095 1096 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1108 1109 1110 1111 1112 1113 1114 1115 1116 1117 1118 1119 1120 1121 1122 1123 1124 1125 1126

Dislich B, Wohlrab F, Bachhuber T, Mu¨ller SA, Kuhn P-H, Hogl S, Meyer-Luehmann M, Lichtenthaler SF (2015) Label-free quantitative proteomics of mouse cerebrospinal fluid detects bsite APP cleaving enzyme (BACE1) protease substrates in vivo. Mol Cell Proteomics 14:2550–2563. https://doi.org/10.1074/mcp. M114.041533. Dityatev A, Bukalo O, Schachner M (2008) Modulation of synaptic transmission and plasticity by cell adhesion and repulsion molecules. Neuron Glia Biol 4:197–209. https://doi.org/10.1017/ S1740925X09990111. Du N, Xu D, Hou X, Song X, Liu C, Chen Y, Wang Y, Li X (2016) Inverse association between serum uric acid levels and Alzheimer’s disease risk. Mol Neurobiol 53:2594–2599. https:// doi.org/10.1007/s12035-015-9271-6. Eggert S, Paliga K, Soba P, Evin G, Masters CL, Weidemann A, Beyreuther K (2004) The proteolytic processing of the amyloid precursor protein gene family members APLP-1 and APLP-2 involves a-, b-, c-, and e-like cleavages. J Biol Chem 279:18146–18156. https://doi.org/10.1074/jbc.M311601200. Faivre-Sarrailh C (2004) Drosophila contactin, a homolog of vertebrate contactin, is required for septate junction organization and paracellular barrier function. Development 131:4931–4942. https://doi.org/10.1242/dev.01372. Faivre-Sarrailh C, Gennarini G, Goridis C, Rougon G (1992) F3/F11 cell surface molecule expression in the developing mouse cerebellum is polarized at synaptic sites and within granule cells. J Neurosci 12:257–267. https://doi.org/10.1523/ JNEUROSCI.12-01-00257.1992. Falk J, Bonnon C, Girault JA, Faivre-Sarrailh C (2002) F3/contactin, a neuronal cell adhesion molecule implicated in axogenesis and myelination. Biol Cell 94:327–334. https://doi.org/10.1016/S02484900(02)00006-0. Fan L Feng, Xu D En, Wang W Hua, Yan K, Wu H, Yao X Qin, Xu R Xiang, Liu C Feng, Ma Q Hong (2013) Caspr interaction with Amyloid Precursor Protein reduces amyloid-b generation in vitro. Neurosci Lett 548:255–260. https://doi.org/10.1016/j. neulet.2013.05.055. Fernandes D, Santos SD, Coutinho E, Whitt JL, Beltra˜o N, Ronda˜o T, Leite MI, Buckley C, Lee H-K, Carvalho AL (2019) Disrupted AMPA receptor function upon genetic- or antibody-mediated loss of autism-associated CASPR2. Cereb Cortex. https://doi.org/ 10.1093/cercor/bhz032. Fernandez T, Morgan T, Davis N, Klin A, Morris A, Farhi A, Lifton RP, State MW (2004) Disruption of contactin 4 (CNTN4) results in developmental delay and other features of 3p deletion syndrome. Am J Hum Genet 74:1286–1293. https://doi.org/10.1086/421474. Flanagan EP, McKeon A, Lennon VA, Boeve BF, Trenerry MR, Tan KM, Drubach DA, Josephs KA, Britton JW, Mandrekar JN, Lowe V, Parisi JE, Pittock SJ (2010) Autoimmune dementia: clinical course and predictors of immunotherapy response. Mayo Clin Proc 85:881–897. https://doi.org/10.4065/mcp.2010.0326. Frere S, Slutsky I (2018) Alzheimer’s disease: from firing instability to homeostasis network collapse. Neuron 97:32–58. https://doi.org/ 10.1016/j.neuron.2017.11.028. Furley AJ, Morton SB, Manalo D, Karagogeos D, Dodd J, Jessell TM (1990) The axonal glycoprotein TAG-1 is an immunoglobulin superfamily member with neurite outgrowth-promoting activity. Cell 61:157–170. https://doi.org/10.1016/0092-8674(90)90223-2. Ganot P, Zoccola D, Tambutte´ E, Voolstra CR, Aranda M, Allemand D, Tambutte´ S (2015) Structural molecular components of septate junctions in cnidarians point to the origin of epithelial junctions in eukaryotes. Mol Biol Evol 32:44–62. https://doi.org/ 10.1093/molbev/msu265. Gao R, Zaccard CR, Shapiro LP, Dionisio LE, Martin-de-Saavedra MD, Piguel NH, Pratt CP, Horan KE, Penzes P (2019) The CNTNAP2-CASK complex modulates GluA1 subcellular distribution in interneurons. Neurosci Lett 701:92–99. https://doi. org/10.1016/j.neulet.2019.02.025. Gautam V, D’Avanzo C, Hebisch M, Kovacs DM, Kim DY (2014) BACE1 activity regulates cell surface contactin-2 levels. Mol Neurodegener 9:1–10. https://doi.org/10.1186/1750-1326-9-4.

13

Gilbert J, Shu S, Yang X, Lu Y, Zhu LQ, Man HY (2016) b- Amyloid triggers aberrant over-scaling of homeostatic synaptic plasticity. Acta Neuropathol Commun 4:1–14. https://doi.org/10.1186/ s40478-016-0398-0. Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, Wood S, Zhang H, Estes A, Brune CW, Bradfield JP, Imielinski M, Frackelton EC, Reichert J, Crawford EL, Munson J, Sleiman PMA, Chiavacci R, Annaiah K, Thomas K, Hou C, Glaberson W, Flory J, Otieno F, Garris M, Soorya L, Klei L, Piven J, Meyer KJ, Anagnostou E, Sakurai T, Game RM, Rudd DS, Zurawiecki D, McDougle CJ, Davis LK, Miller J, Posey DJ, Michaels S, Kolevzon A, Silverman JM, Bernier R, Levy SE, Schultz RT, Dawson G, Owley T, McMahon WM, Wassink TH, Sweeney JA, Nurnberger JI, Coon H, Sutcliffe JS, Minshew NJ, Grant SFA, Bucan M, Cook EH, Buxbaum JD, Devlin B, Schellenberg GD, Hakonarson H (2009) Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459:569–573. https://doi.org/ 10.1038/nature07953. Gokce O, Sudhof TC (2013) Membrane-tethered monomeric neurexin LNS-domain triggers synapse formation. J Neurosci 33:14617–14628. https://doi.org/10.1523/JNEUROSCI.123213.2013. Gollan L, Salomon D, Salzer JL, Peles E (2003) Caspr regulates the processing of contactin and inhibits its binding to neurofascin. J Cell Biol 163:1213–1218. https://doi.org/10.1083/jcb.200309147. Gresa-Arribas N, Planaguma` J, Petit-Pedrol M, Kawachi I, Katada S, Glaser CA, Simabukuro MM, Armangue´ T, Martı´ nez-Herna´ndez E, Graus F, Dalmau J (2016) Human neurexin-3a antibodies associate with encephalitis and alter synapse development. Neurology 86:2235–2242. https://doi.org/10.1212/ WNL.0000000000002775. Gulisano W, Bizzoca A, Gennarini G, Palmeri A, Puzzo D (2017) Role of the adhesion molecule F3/Contactin in synaptic plasticity and memory. Mol Cell Neurosci 81:64–71. https://doi.org/10.1016/j. mcn.2016.12.003. Guntupalli S, Widagdo J, Anggono V (2016) Amyloid-b-induced dysregulation of AMPA receptor trafficking. Neural Plast 2016. https://doi.org/10.1155/2016/3204519. Haass C, Kaether C, Thinakaran G, Sisodia S (2012) Trafficking and proteolytic processing of APP. Cold Spring Harb Perspect Med 2. https://doi.org/10.1101/cshperspect.a006270. Hardy J, De Strooper B (2017) Alzheimer’s disease: where next for anti-amyloid therapies? Brain 140:853–855. https://doi.org/ 10.1093/brain/awx059. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to the amyloid hypothesis of Alzheim progress and problems on the road to. Science (80-) 297:353–356. https://doi.org/ 10.1126/science.1072994. Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schu¨rmann B, Heun R, Van Den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Fro¨lich L, Hampel H, Hu¨ll M, Rujescu D, Goate AM, Kauwe JSK, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Mu¨hleisen TW, No¨then MM, Moebus S, Jo¨ckel KH, Klopp N, Wichmann HE, Carrasquillo MM, Pankratz VS, Younkin SG, O’Donovan M, Owen MJ, Williams J (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet 41:1088–1093. https://doi.org/10.1038/ng.440. Heber S, Herms J, Gajic V, Hainfellner J, Aguzzi A, Ru¨licke T, von Kretzschmar H, von Koch C, Sisodia S, Tremml P, Lipp HP, Wolfer DP, Mu¨ller U (2000) Mice with combined gene knock-outs

Please cite this article in press as: Bamford RA et al. The Interaction Between Contactin and Amyloid Precursor Protein and Its Role in Alzheimer’s Disease. Neuroscience (2019), https://doi.org/10.1016/j. neuroscience.2019.10.006

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R. A. Bamford et al. / Neuroscience xxx (2019) xxx–xxx

reveal essential and partially redundant functions of amyloid precursor protein family members. J Neurosci 20:7951–7963. Henley JM, Wilkinson KA (2016) Synaptic AMPA receptor composition in development, plasticity and disease. Nat Rev Neurosci 17:337–350. https://doi.org/10.1038/nrn.2016.37. Herms J, Anliker B, Heber S, Ring S, Fuhrmann M, Kretzschmar H, Sisodia S, Mu¨ller U (2004) Cortical dysplasia resembling human type 2 lissencephaly in mice lacking all three APP family members. EMBO J 23:4106–4115. https://doi.org/10.1038/sj. emboj.7600390. Hirano A, Ohara T, Takahashi A, Aoki M, Fuyuno Y, Ashikawa K, Morihara T, Takeda M, Kamino K, Oshima E, Okahisa Y, Shibata N, Arai H, Akatsu H, Ikeda M, Iwata N, Ninomiya T, Monji A, Kitazono T, Kiyohara Y, Kubo M, Kanba S (2015) A genome-wide association study of late-onset Alzheimer’s disease in a Japanese population. Psychiatr Genet 25:139–146. https://doi.org/10.1097/ YPG.0000000000000090. Ho A, Su¨dhof TC (2004) Binding of F-spondin to amyloid-beta precursor protein: a candidate amyloid-beta precursor protein ligand that modulates amyloid-beta precursor protein cleavage. Proc Natl Acad Sci USA 101:2548–2553. Hoe H-S, Lee KJ, Carney RSE, Lee J, Markova A, Lee J-Y, Howell BW, Hyman BT, Pak DTS, Bu G, Rebeck GW (2009a) Interaction of reelin with amyloid precursor protein promotes neurite outgrowth. J Neurosci 29:7459–7473. https://doi.org/10.1523/ JNEUROSCI.4872-08.2009. Hoe HS, Fu Z, Makarova A, Lee JY, Lu C, Feng L, Pajoohesh-Ganji A, Matsuoka Y, Hyman BT, Ehlers MD, Vicini S, Pak DTS, Rebeck GW (2009b) The effects of amyloid precursor protein on postsynaptic composition and activity. J Biol Chem 284:8495–8506. https://doi.org/10.1074/jbc.M900141200. Hoe HS, Lee HK, Pak DTS (2012) The upside of APP at synapses. CNS Neurosci Ther 18:47–56. https://doi.org/10.1111/j.17555949.2010.00221.x. Horresh I, Poliak S, Grant S, Bredt D, Rasband MN, Peles E (2008) Multiple molecular interactions determine the clustering of Caspr2 and Kv1 channels in myelinated axons. J Neurosci 28:14213–14222. https://doi.org/10.1523/JNEUROSCI.339808.2008. Hsia AY, Masliah E, McConlogue L, Yu GQ, Tatsuno G, Hu K, Kholodenko D, Malenka RC, Nicoll RA, Mucke L (1999) Plaqueindependent disruption of neural circuits in Alzheimer’s disease mouse models. Proc Natl Acad Sci USA 96:3228–3233. Hu J, Liao J, Sathanoori M, Kochmar S, Sebastian J, Yatsenko SA, Surti U (2015) CNTN6 copy number variations in 14 patients: a possible candidate gene for neurodevelopmental and neuropsychiatric disorders. J Neurodev Disord 7:1–9. https://doi. org/10.1186/s11689-015-9122-9. Huang Y, Tanimukai H, Liu F, Iqbal K, Grundke-Iqbal I, Gong CX (2004) Elevation of the level and activity of acid ceramidase in Alzheimer’s disease brain. Eur J Neurosci 20:3489–3497. https:// doi.org/10.1111/j.1460-9568.2004.03852.x. Huang YWA, Zhou B, Wernig M, Su¨dhof TC (2017) ApoE2, ApoE3, and ApoE4 differentially stimulate APP transcription and Ab secretion. Cell 168:427–441.e21. https://doi.org/10.1016/ j.cell.2016.12.044. Huang Z, Yu Y, Shimoda Y, Watanabe K, Liu Y (2012) Loss of neural recognition molecule NB-3 delays the normal projection and terminal branching of developing corticospinal tract axons in the mouse. J Comp Neurol 520:1227–1245. https://doi.org/10.1002/ cne.22772. Hur J-Y, Teranishi Y, Kihara T, Yamamoto NG, Inoue M, Hosia W, Hashimoto M, Winblad B, Frykman S, Tjernberg LO (2012) Identification of novel c-secretase-associated proteins in detergent-resistant membranes from brain. J Biol Chem 287:11991–12005. https://doi.org/10.1074/jbc.M111.246074. Iakoubov L, Mossakowska M, Szwed M, Duan Z, Sesti F (2013) A common copy number variation (CNV) polymorphism in the CNTNAP4 gene: association with aging in females. PLoS One 8:1–9. https://doi.org/10.1371/journal.pone.0079790.

Iakoubov L, Mossakowska M, Szwed M, Puzianowska-Kuznicka M (2015) A common copy number variation polymorphism in the CNTNAP2 gene: Sexual dimorphism in association with healthy aging and disease. Gerontology 61:24–31. https://doi.org/ 10.1159/000363320. Jacobsen KT, Iverfeldt K (2009) Amyloid precursor protein and its homologues: a family of proteolysis-dependent receptors. Cell Mol Life Sci 66:2299–2318. https://doi.org/10.1007/s00018-0090020-8. Jurgensen S, Castillo PE (2015) Selective dysregulation of hippocampal inhibition in the mouse lacking autism candidate gene CNTNAP2. J Neurosci 35:14681–14687. https://doi.org/ 10.1523/JNEUROSCI.1666-15.2015. Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R (2003) APP processing and synaptic function. Neuron 37:925–937. https://doi.org/10.1016/S08966273(03)00124-7. Kaneko-Goto T, Yoshihara S-I, Miyazaki H, Yoshihara Y (2008) BIG2 mediates olfactory axon convergence to target glomeruli. Neuron 57:834–846. https://doi.org/10.1016/j. neuron.2008.01.023. Kashani A, Lepicard E`, Poirel O, Videau C, David JP, Fallet-Bianco C, Simon A, Delacourte A, Giros B, Epelbaum J, Betancur C, El Mestikawy S (2008) Loss of VGLUT1 and VGLUT2 in the prefrontal cortex is correlated with cognitive decline in Alzheimer disease. Neurobiol Aging 29:1619–1630. https://doi.org/10.1016/ j.neurobiolaging.2007.04.010. Katidou M, Tavernarakis N, Karagogeos D (2013) The contactin RIG6 mediates neuronal and non-neuronal cell migration in Caenorhabditis elegans. Dev Biol 373:184–195. https://doi.org/ 10.1016/j.ydbio.2012.10.027. Kimberly WT, Zheng JB, Gue´nette SY, Selkoe DJ (2001) The intracellular domain of the b-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notchlike manner. J Biol Chem 276:40288–40292. https://doi.org/ 10.1074/jbc.C100447200. Kizuka Y, Kitazume S, Fujinawa R, Saito T, Iwata N, Saido TC, Nakano M, Yamaguchi Y, Hashimoto Y, Staufenbiel M, Hatsuta H, Murayama S, Manya H, Endo T, Taniguchi N (2015) An aberrant sugar modification of BACE1 blocks its lysosomal targeting in Alzheimer’s disease. EMBO Mol Med 7:175–189. Available from: https://doi.org/10.15252/emmm.201404438. Kleijer KTE, Zuko A, Shimoda Y, Watanabe K, Burbach JPH (2015) Contactin-5 expression during development and wiring of the thalamocortical system. Neuroscience 310:106–113. https://doi. org/10.1016/j.neuroscience.2015.09.039. Klein CJ, Lennon VA, Aston PA, McKeon A, O’Toole O, Quek A, Pittock SJ (2013) Insights from LGI1 and CASPR2 potassium channel complex autoantibody subtyping. JAMA Neurol 70:229. https://doi.org/10.1001/jamaneurol.2013.592. Klevanski M, Herrmann U, Weyer SW, Fol R, Cartier N, Wolfer DP, Caldwell JH, Korte M, Muller UC (2015) The APP intracellular domain is required for normal synaptic morphology, synaptic plasticity, and hippocampus-dependent behavior. J Neurosci 35:16018–16033. https://doi.org/10.1523/JNEUROSCI.200915.2015. Konietzko U (2012) AICD nuclear signaling and its possible contribution to Alzheimer’s disease. Curr Alzheimer Res 9:200–216. Korte M, Herrmann U, Zhang X, Draguhn A (2012) The role of APP and APLP for synaptic transmission, plasticity, and network function: lessons from genetic mouse models. Exp Brain Res 217:435–440. https://doi.org/10.1007/s00221-011-2894-6. Kuhn P-H, Koroniak K, Hogl S, Colombo A, Zeitschel U, Willem M, Volbracht C, Schepers U, Imhof A, Hoffmeister A, Haass C, Roßner S, Bra¨se S, Lichtenthaler SF (2012) Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons. EMBO J 31:3157–3168. https://doi.org/10.1038/ emboj.2012.173.

Please cite this article in press as: Bamford RA et al. The Interaction Between Contactin and Amyloid Precursor Protein and Its Role in Alzheimer’s Disease. Neuroscience (2019), https://doi.org/10.1016/j. neuroscience.2019.10.006

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Kurz A, Perneczky R (2011) Amyloid clearance as a treatment target against Alzheimer’s disease. J Alzheimer’s Dis 24:61–73. https:// doi.org/10.3233/JAD-2011-102139. Kyriakopoulou K, de Diego I, Wassef M, Karagogeos D (2002) A combination of chain and neurophilic migration involving the adhesion molecule TAG-1 in the caudal medulla. Development 129:287–296. https://doi.org/10.1109/IJCNN.2015.7280622. Lancaster E, Huijbers MGM, Bar V, Boronat A, Wong A, MartinezHernandez E, Wilson C, Jacobs D, Lai M, Walker RW, Graus F, Bataller L, Illa I, Markx S, Strauss KA, Peles E, Scherer SS, Dalmau J (2011) Investigations of caspr2, an autoantigen of encephalitis and neuromyotonia. Ann Neurol 69:303–311. https:// doi.org/10.1002/ana.22297. Lee S, Takeda Y, Kawano H, Hosoya H, Nomoto M, Fujimoto D, Takahashi N, Watanabe K (2000) Expression and regulation of a gene encoding neural recognition molecule NB-3 of the contactin/ F3 subgroup in mouse brain. Gene 245:253–266. https://doi.org/ 10.1016/S0378-1119(00)00031-7. Leidinger P, Backes C, Stephaniedeutscherukseu SD, Katjaschmittuniklinikum-SAARLANDDE KS, Sabinemuelleruniklinikum-SAARLANDDE SCM, Karenfresemeduni-Heidelbergde KF, Haas J, Ruprecht K, Paul F, Stahler C, Christophlanguk-Erlangende CJGL, Benjaminmedermeduni-Heidelbergde BM, Bartfai T, Meese E (2013) A blood based 12-miRNA signature of Alzheimer disease patients article type. Genome Biol. https://doi.org/10.1186/gb2013-14-7-r78. Leshchynska I, Sytnyk V (2016) Synaptic cell adhesion molecules in Alzheimer’s disease. Neural Plast 2016:1–9. https://doi.org/ 10.1155/2016/6427537. Li H, Takeda Y, Niki H, Ogawa J, Kobayashi S, Kai N, Akasaka K, Asano M, Sudo K, Iwakura Y, Watanabe K (2003) Aberrant responses to acoustic stimuli in mice deficient for neural recognition molecule NB-2. Eur J Neurosci 17:929–936. https:// doi.org/10.1046/j.1460-9568.2003.02514.x. Li H, Wetten S, Li L, St. Jean PL, Upmanyu R, Surh L, Hosford D, Barnes MR, Briley JD, Borrie M, Coletta N, Delisle R, Dhalla D, Ehm MG, Feldman HH, Fornazzari L, Gauthier S, Goodgame N, Guzman D, Hammond S, Hollingworth P, Hsiung G-Y, Johnson J, Kelly DD, Keren R, Kertesz A, King KS, Lovestone S, Loy-English I, Matthews PM, Owen MJ, Plumpton M, Pryse-Phillips W, Prinjha RK, Richardson JC, Saunders A, Slater AJ, St. George-Hyslop PH, Stinnett SW, Swartz JE, Taylor RL, Wherrett J, Williams J, Yarnall DP, Gibson RA, Irizarry MC, Middleton LT, Roses AD (2008) Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease. Arch. Neurol. 65. https://doi.org/10.1001/archneurol.2007.3. Lorenzetto E, Moratti E, Vezzalini M, Harroch S, Sorio C, Buffelli M (2014) Distribution of different isoforms of receptor protein tyrosine phosphatase?? (Ptprg-RPTP??) in adult mouse brain: upregulation during neuroinflammation. Brain Struct Funct 219:875–890. https://doi.org/10.1007/s00429-013-0541-7. Lourenc¸o FC, Galvan V, Fombonne J, Corset V, Llambi F, Mu¨ller U, Bredesen DE, Mehlen P (2009) Netrin-1 interacts with amyloid precursor protein and regulates amyloid-b production. Cell Death Differ 16:655–663. https://doi.org/10.1038/cdd.2008.191. Lu Z, Reddy MVVVS, Liu J, Kalichava A, Liu J, Zhang L, Chen F, Wang Y, Holthauzen LMF, White MA, Seshadrinathan S, Zhong X, Ren G, Rudenko G (2016) Molecular architecture of contactinassociated protein-like 2 (CNTNAP2) and its interaction with contactin 2 (CNTN2). J Biol Chem 291:24133–24147. https://doi. org/10.1074/jbc.M116.748236. Ludewig S, Korte M (2017) Novel insights into the physiological function of the APP (Gene) family and its proteolytic fragments in synaptic plasticity. Front Mol Neurosci 9. https://doi.org/10.3389/ fnmol.2016.00161. Ma Q-H, Bagnard D, Xiao Z-C, Dawe GS (2008a) A TAG on to the neurogenic functions of APP. Cell Adhes Migr 2:2–8. https://doi. org/10.4161/cam.2.1.5790. Ma QH, Futagawa T, Yang WL, Jiang XD, Zeng L, Takeda Y, Xu RX, Bagnard D, Schachner M, Furley AJ, Karagogeos D, Watanabe

15

K, Dawe GS, Xiao ZC (2008b) A TAG1-APP signalling pathway through Fe65 negatively modulates neurogenesis. Nat Cell Biol 10:283–294. https://doi.org/10.1038/ncb1690. Masters CL, Bateman R, Blennow K, Rowe CC, Sperling RA, Cummings JL (2015) Alzheimer’s disease. Nat Rev Dis Prim 1:1–18. https://doi.org/10.1038/nrdp.2015.56. Mattson MP (2004) Pathways towards and away from Alzheimer’s disease. Nature 430:631–639. https://doi.org/ 10.1038/nature02621. Mattson MP, van Praag H (2008) TAGing APP constrains neurogenesis. Nat Cell Biol 10:249–250. https://doi.org/10.1038/ ncb0308-249. McKeon A (2016) Autoimmune encephalopathies and dementias. Contin Lifelong Learn Neurol 22:538–558. https://doi.org/10.1212/ CON.0000000000000299. Medway C, Shi H, Bullock J, Black H, Brown K, Vafadar-isfahani B, Matharoo-ball B, Ball G, Rees R, Kalsheker N, Morgan K (2010) Original Article Using In silico LD clumping and meta-analysis of genome-wide datasets as a complementary tool to investigate and validate new candidate biomarkers in Alzheimer’s disease. Int J 1:134–144. Midthune B, Tyan SH, Walsh JJ, Sarsoza F, Eggert S, Hof PR, Dickstein DL, Koo EH (2012) Deletion of the amyloid precursorlike protein 2 (APLP2) does not affect hippocampal neuron morphology or function. Mol Cell Neurosci 49:448–455. https:// doi.org/10.1016/j.mcn.2012.02.001. Milanese C, Fiumara F, Bizzoca A, Giachello C, Leitinger G, Gennarini G, Montarolo PG, Ghirardi M (2008) F3/contactinrelated proteins in Helix pomatia nervous tissue (HCRPs): Distribution and function in neurite growth and neurotransmitter release. J Neurosci Res 86:821–831. https://doi.org/10.1002/ jnr.21539. Mohebiany AN, Harroch S, Bouyain S (2014) New Insights into the roles of the contactin cell adhesion molecules in neural development. Adv Neurbiol:165–194. https://doi.org/10.1007/ 978-1-4614-8090-7_8. Mousavi M, Jonsson P, Antti H, Adolfsson R, Nordin A, Bergdahl J, Eriksson K, Moritz T, Nilsson L-G, Nyberg L (2014) Serum metabolomic biomarkers of dementia. Dement Geriatr Cognit Dis Extra 4:252–262. https://doi.org/10.1159/000364816. Mucke L, Masliah E, Yu G-Q, Mallory M, Rockenstein EM, Tatsuno G, Hu K, Kholodenko D, Johnson-Wood K, McConlogue L (2000) High-level neuronal expression of Ab 1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 20:4050–4058. https://doi.org/ 10.1523/JNEUROSCI.20-11-04050.2000. Mu¨ller UC, Deller T, Korte M (2017) Not just amyloid: physiological functions of the amyloid precursor protein family. Nat Rev Neurosci 18:281–298. https://doi.org/10.1038/nrn.2017.29. Mu¨ller UC, Zheng H (2012) Physiological functions of APP family proteins. Cold Spring Harb Perspect Med 2:1–17. https://doi.org/ 10.1101/cshperspect.a006288. Murai KK, Misner D, Ranscht B (2002) Contactin supports synaptic plasticity associated with hippocampal long-term depression but not potentiation. Curr Biol 12:181–190. https://doi.org/10.1016/ S0960-9822(02)00680-2. Nelson AR, Sweeney MD, Sagare AP, Zlokovic BV (2016) Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer’s disease. Biochim Biophys Acta Mol Basis Dis 1862:887–900. https://doi.org/10.1016/j.bbadis.2015.12.016. Nicolas M, Hassan BA (2014) Amyloid precursor protein and neural development. Development 141:2543–2548. https://doi.org/ 10.1242/dev.108712. Ogawa J, Lee S, Itoh K, Nagata S, Machida T, Takeda Y, Watanabe K (2001) Neural recognition molecule NB-2 of the contactin/F3 subgroup in rat: Specificity in neurite outgrowth-promoting activity and restricted expression in the brain regions. J Neurosci Res 65:100–110. https://doi.org/10.1002/jnr.1133. Oguro-Ando A, Zuko A, Kleijer KTE, Burbach JPH (2017) A current view on contactin-4, -5, and -6: Implications in

Please cite this article in press as: Bamford RA et al. The Interaction Between Contactin and Amyloid Precursor Protein and Its Role in Alzheimer’s Disease. Neuroscience (2019), https://doi.org/10.1016/j. neuroscience.2019.10.006

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R. A. Bamford et al. / Neuroscience xxx (2019) xxx–xxx

neurodevelopmental disorders. Mol Cell Neurosci 81:72–83. https://doi.org/10.1016/j.mcn.2016.12.004. Osterfield M, Egelund R, Young L, Flanagan J (2008) Interaction of amyloid precursor protein with contactins and NgCAM in the retinotectal system. Development 135:1189–1199. https://doi.org/ 10.1242/dev.007401. Osterhout JA, Stafford BK, Nguyen PL, Yoshihara Y, Huberman AD (2015) Contactin-4 mediates axon-target specificity and functional development of the accessory optic system. Neuron 86:985–999. https://doi.org/10.1016/j.neuron.2015.04.005. Palop JJ, Mucke L (2010) Amyloid-beta induced neuronal disease: from synapses toward neural networks. Nat Neurosci 13:812–818. https://doi.org/10.1038/nn.2583.Amyloid-. Parra-Damas A, Saura CA (2019) Synapse-to-nucleus signaling in neurodegenerative and neuropsychiatric disorders. Biol Psychiatry 1–10. https://doi.org/10.1016/j.biopsych.2019.01.006. Peles E (1997) Identification of a novel contactin-associated transmembrane receptor with multiple domains implicated in protein-protein interactions. EMBO J 16:978–988. https://doi.org/ 10.1093/emboj/16.5.978. Peles E, Joho K, Plowman GD, Schlessinger J (1997) Close similarity between drosophila neurexin IV and mammalian caspr protein suggests a conserved mechanism for cellular interactions. Cell 88:745–746. https://doi.org/10.1016/S0092-8674(00)81920-0. Peles E, Salzer JL (2000) Molecular domains of myelinated axons. Curr Opin Neurobiol 10:558–565. https://doi.org/10.1016/S09594388(00)00122-7. Petersen ME, O’Bryant S (2019) Blood based biomarkers for down syndrome and Alzheimer’s disease. A systematic review. Dev Neurobiol dneu.22714. https://doi.org/10.1002/dneu.22714. Poliak S, Gollan L, Martinez R, Custer A, Einheber S, Salzer JL, Trimmer JS, Shrager P, Peles E (1999) Caspr2, a new member of the Neurexin superfamily, is localized at the juxtaparanodes of myelinated axons and associates with K+ channels. Neuron 24:1037–1047. https://doi.org/10.1016/S0896-6273(00)81049-1. Poliak S, Gollan L, Salomon D, Berglund EO, Ohara R, Ranscht B, Peles E (2001) Localization of Caspr2 in myelinated nerves depends on axon-glia interactions and the generation of barriers along the axon. J Neurosci 21:7568–7575. Poliak S, Salomon D, Elhanany H, Sabanay H, Kiernan B, Pevny L, Stewart CL, Xu X, Chiu SY, Shrager P, Furley AJW, Peles E (2003) Juxtaparanodal clustering of Shaker-like K+channels in myelinated axons depends on Caspr2 and TAG-1. J Cell Biol 162:1149–1160. https://doi.org/10.1083/jcb.200305018. Poot M (2015) Connecting the CNTNAP2 networks with neurodevelopmental disorders. Mol Syndromol 6:7–22. https:// doi.org/10.1159/000371594. Pramatarova A, Chen K, Howell BW (2008) A genetic interaction between the APP and Dab1 genes influences brain development. Mol Cell Neurosci 37:178–186. https://doi.org/10.1016/j. mcn.2007.09.008. Pratt KG, Zimmerman EC, Cook DG, Sullivan JM (2011) Presenilin 1 regulates homeostatic synaptic scaling through Akt signaling. Nat Neurosci 14:1112–1114. https://doi.org/10.1038/nn.2893. Priller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar HA, Herms J (2006) Synapse formation and function is modulated by the amyloid precursor protein. J Neurosci 26:7212–7221. https://doi. org/10.1523/JNEUROSCI.1450-06.2006. Prince M, Knapp M, Guerchet M, McCrone P, Prina M, ComasHerrera A, Wittenberg R, Adelaja B, Hu B, King D, Rehill A, Salimkumar D (2014) Dementia UK: update, Igarss 2014. Alzheimer’s Society. https://doi.org/10.1007/s13398-014-01737.2. Puzzo D, Bizzoca A, Loreto C, Guida CA, Gulisano W, Frasca G, Bellomo M, Castorina S, Gennarini G, Palmeri A (2015) Role of F3/contactin expression profile in synaptic plasticity and memory in aged mice. Neurobiol Aging 36:1702–1715. https://doi.org/ 10.1016/j.neurobiolaging.2015.01.004. Puzzo D, Bizzoca A, Privitera L, Furnari D, Giunta S, Girolamo F, Pinto M, Gennarini G, Palmeri A (2013) F3/Contactin promotes hippocampal neurogenesis, synaptic plasticity, and memory in

adult mice. Hippocampus 23:1367–1382. https://doi.org/10.1002/ hipo.22186. Puzzo D, Loreto C, Giunta S, Musumeci G, Frasca G, Podda MV, Arancio O, Palmeri A (2014) Effect of phosphodiesterase-5 inhibition on apoptosis and beta amyloid load in aged mice. Neurobiol Aging 35:520–531. https://doi.org/10.1016/j. neurobiolaging.2013.09.002. Ramaker JM, Swanson TL, Copenhaver PF (2016) Manduca contactin regulates amyloid precursor protein-dependent neuronal migration. J Neurosci 36:8757–8775. https://doi.org/ 10.1523/JNEUROSCI.0729-16.2016. Ramaker JM, Swanson TL, Copenhaver PF (2013) Amyloid precursor proteins interact with the heterotrimeric G protein go in the control of neuronal migration. J Neurosci 33:10165–10181. https://doi.org/10.1523/JNEUROSCI.1146-13.2013. Reiman EM, Webster JA, Myers AJ, Hardy J, Dunckley T, Zismann VL, Joshipura KD, Pearson JV, Hu-Lince D, Huentelman MJ, Craig DW, Coon KD, Liang WS, Herbert RH, Beach T, Rohrer KC, Zhao AS, Leung D, Bryden L, Marlowe L, Kaleem M, Mastroeni D, Grover A, Heward CB, Ravid R, Rogers J, Hutton ML, Melquist S, Petersen RC, Alexander GE, Caselli RJ, Kukull W, Papassotiropoulos A, Stephan DA (2007) GAB2 alleles modify Alzheimer’s risk in APOE e4 carriers. Neuron 54:713–720. https:// doi.org/10.1016/j.neuron.2007.05.022. Reitz C (2012) Alzheimer’s disease and the amyloid cascade hypothesis: a critical review. Int J Alzheimers Dis 2012. https:// doi.org/10.1155/2012/369808. Rice HC, de Malmazet D, Schreurs A, Frere S, Van Molle I, Volkov AN, Creemers E, Vertkin I, Nys J, Ranaivoson FM, Comoletti D, Savas JN, Remaut H, Balschun D, Wierda KD, Slutsky I, Farrow K, De Strooper B, de Wit J (2019a) Secreted amyloid-b precursor protein functions as a GABA B R1a ligand to modulate synaptic transmission. Science (80-) 363. https://doi.org/10.1126/science. aao4827. eaao4827. Rice HC, Townsend M, Bai J, Suth S, Cavanaugh W, Selkoe DJ, Young-Pearse TL (2012) Pancortins interact with amyloid precursor protein and modulate cortical cell migration. Development 139:3986–3996. https://doi.org/10.1242/ dev.082909. Rice HC, Young-Pearse TL, Selkoe DJ (2013) Systematic evaluation of candidate ligands regulating ectodomain shedding of Amyloid precursor protein. Biochemistry 52:3264–3277. https://doi.org/ 10.1021/bi400165f. Rodriguez-Perdigon M, Tordera RM, Gil-Bea FJ, Gerenu G, Ramirez MJ, Solas M (2016) Down-regulation of glutamatergic terminals (VGLUT1) driven by Ab in Alzheimer’s disease. Hippocampus 26:1303–1312. https://doi.org/10.1002/hipo.22607. Roohi J, Montagna C, Tegay DH, Palmer LE, DeVincent C, Pomeroy JC, Christian SL, Nowak N, Hatchwell E (2008) Disruption of contactin 4 in three subjects with autism spectrum disorder. J Med Genet 46:176–182. https://doi.org/10.1136/jmg.2008.057505. Ross CA, Poirier MA (2004) Protein aggregation and neurodegenerative disease. Nat Med 10:S10–S17. https://doi. org/10.1038/nm1066. Saifetiarova J, Liu X, Taylor AM, Li J, Bhat MA (2017) Axonal domain disorganization in Caspr1 and Caspr2 mutant myelinated axons affects neuromuscular junction integrity, leading to muscle atrophy. J Neurosci Res 95:1373–1390. https://doi.org/10.1002/ jnr.24052. Saint-Martin M, Joubert B, Pellier-Monnin V, Pascual O, Noraz N, Honnorat J (2018) Contactin-associated protein-like 2, a protein of the neurexin family involved in several human diseases. Eur J Neurosci 48:1906–1923. https://doi.org/10.1111/ejn.14081. Sakurai K, Toyoshima M, Takeda Y, Shimoda Y, Watanabe K (2010) Synaptic formation in subsets of glutamatergic terminals in the mouse hippocampal formation is affected by a deficiency in the neural cell recognition molecule NB-3. Neurosci Lett 473:102–106. https://doi.org/10.1016/j.neulet.2010.02.027. Sakurai K, Toyoshima M, Ueda H, Matsubara K, Takeda Y, Karagogeos D, Shimoda Y, Watanabe K (2009) Contribution of the neural cell recognition molecule NB-3 to synapse formation

Please cite this article in press as: Bamford RA et al. The Interaction Between Contactin and Amyloid Precursor Protein and Its Role in Alzheimer’s Disease. Neuroscience (2019), https://doi.org/10.1016/j. neuroscience.2019.10.006

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between parallel fibers and Purkinje cells in mouse. Dev Neurobiol 69:811–824. https://doi.org/10.1002/dneu.20742. Salzer JL, Brophy PJ, Peles E (2008) Molecular domains of myelinated axons in the peripheral nervous system. Glia 56:1532–1540. https://doi.org/10.1002/glia.20750. Santos SD, Iuliano O, Ribeiro L, Veran J, Ferreira JS, Rio P, Mulle C, Duarte CB, Carvalho AL (2012) Contactin-associated protein 1 (Caspr1) regulates the traffic and synaptic content of a-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors. J Biol Chem 287:6868–6877. https://doi. org/10.1074/jbc.M111.322909. Saura CA, Choi S-Y, Beglopoulos V, Malkani S, Zhang D, Rao BSS, Chattarji S, Kelleher RJ, Kandel ER, Duff K, Kirkwood A, Shen J (2004) Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Neuron 42:23–36. https://doi.org/10.1016/ S0896-6273(04)00182-5. Savvaki M, Panagiotaropoulos T, Stamatakis A, Sargiannidou I, Karatzioula P, Watanabe K, Stylianopoulou F, Karagogeos D, Kleopa KA (2008) Impairment of learning and memory in TAG-1 deficient mice associated with shorter CNS internodes and disrupted juxtaparanodes. Mol Cell Neurosci 39:478–490. https://doi.org/10.1016/j.mcn.2008.07.025. Schauenburg L, Liebsch F, Eravci M, Mayer MC, Weise C, Multhaup G (2018) APLP1 is endoproteolytically cleaved by c-secretase without previous ectodomain shedding. Sci Rep 8:1916. https:// doi.org/10.1038/s41598-018-19530-8. Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton M, Kukull W, Larson E, Levy-Lahad E, Viitanen M, Peskind E, Poorkaj P, Schellenberg G, Tanzi R, Wasco W, Lannfelt L, Selkoe D, Younkin S (1996) Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat Med 2:864–870. Schilling S, Mehr A, Ludewig S, Stephan J, Zimmermann M, August A, Strecker P, Korte M, Koo EH, Mu¨ller UC, Kins S, Eggert S (2017) APLP1 Is a synaptic cell adhesion molecule, supporting maintenance of dendritic spines and basal synaptic transmission. J Neurosci 37:5345–5365. https://doi.org/10.1523/ JNEUROSCI.1875-16.2017. Schrenk-Siemens K, Perez-Alcala S, Richter J, Lacroix E, Rahuel J, Korte M, Mu¨ller U, Barde Y-A, Bibel M (2008) Embryonic stem cell-derived neurons as a cellular system to study gene function: lack of amyloid precursor proteins APP and APLP2 leads to defective synaptic transmission. Stem Cells 26:2153–2163. https://doi.org/10.1634/stemcells.2008-0010. Scott-Van Zeeland AA, Abrahams BS, Alvarez-Retuerto AI, Sonnenblick LI, Rudie JD, Ghahremani D, Mumford JA, Poldrack RA, Dapretto M, Geschwind DH, Bookheimer SY (2010) Altered functional connectivity in frontal lobe circuits is associated with variation in the autism risk gene CNTNAP2. Sci Transl Med 2. https://doi.org/10.1126/scitranslmed.3001344. Selkoe DJ (1999) Translating cell biology into therapeutic advances in Alzheimer’s disease. Nature 399:A23–A31. https://doi.org/ 10.1038/399a023. Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 8:595–608. Available from: https://doi.org/10.15252/emmm.201606210. Shariati SAM, Lau P, Hassan BA, Muller U, Dotti CG, De Strooper B, Gartner A (2013) APLP2 regulates neuronal stem cell differentiation during cortical development. J Cell Sci 126:1268–1277. https://doi.org/10.1242/jcs.122440. Sherman DL, Tait S, Melrose S, Johnson R, Zonta B, Court FA, Macklin WB, Meek S, Smith AJH, Cottrell DF, Brophy PJ (2005) Neurofascins are required to establish axonal domains for saltatory conduction. Neuron 48:737–742. https://doi.org/ 10.1016/j.neuron.2005.10.019. Shimoda Y, Koseki F, Itoh M, Toyoshima M, Watanabe K (2012) A cis-complex of NB-2/contactin-5 with amyloid precursor-like

17

protein 1 is localized on the presynaptic membrane. Neurosci Lett 510:148–153. https://doi.org/10.1016/j.neulet.2012.01.026. Shimoda Y, Watanabe K (2009) Contactins. Cell Adhes Migr 3:64–70. https://doi.org/10.4161/cam.3.1.7764. Soba P, Eggert S, Wagner K, Zentgraf H, Siehl K, Kreger S, Lo¨wer A, Langer A, Merdes G, Paro R, Masters CL, Mu¨ller U, Kins S, Beyreuther K (2005) Homo- and heterodimerization of APP family members promotes intercellular adhesion. EMBO J 24:3624–3634. https://doi.org/10.1038/sj.emboj.7600824. Sosa LJ, Bergman J, Estrada-Bernal A, Glorioso TJ, Kittelson JM, Pfenninger KH (2013) Amyloid precursor protein is an autonomous growth cone adhesion molecule engaged in contact guidance. PLoS One 8:1–16. https://doi.org/10.1371/ journal.pone.0064521. Sosa LJ, Ca´ceres A, Dupraz S, Oksdath M, Quiroga S, Lorenzo A (2017) The physiological role of the amyloid precursor protein as an adhesion molecule in the developing nervous system. J Neurochem 143:11–29. https://doi.org/10.1111/jnc.14122. Spiegel I, Salomon D, Erne B, Schaeren-Wiemers N, Peles E (2002) Caspr3 and caspr4, two novel members of the caspr family are expressed in the nervous system and interact with PDZ domains. Mol Cell Neurosci 20:283–297. Spitsin S, Koprowski H (2010) Role of uric acid in Alzheimer’s disease. J Alzheimer’s Dis 19:1337–1338. https://doi.org/ 10.3233/JAD-2010-1336. Styr B, Slutsky I (2018) Imbalance between firing homeostasis and synaptic plasticity drives early-phase Alzheimer’s disease. Nat Neurosci 21:463–473. https://doi.org/10.1038/s41593-018-0080x. Suter DM, Pollerberg GE, Buchstaller A, Giger RJ, Dreyer WJ, Sonderegger P (1995) Binding between the neural cell adhesion molecules axonin-1 and Nr-CAM/Bravo is involved in neuron-glia interaction. J Cell Biol 131:1067–1081. https://doi.org/10.5167/ uzh-1110. Swanson TL, Knittel LM, Coate TM, Farley SM, Snyder MA, Copenhaver PF (2005) The insect homologue of the amyloid precursor protein interacts with the heterotrimeric G protein Go alpha in an identified population of migratory neurons. Dev Biol 288:160–178. https://doi.org/10.1016/j.ydbio.2005.09.029. Tachi N, Hashimoto Y, Nawa M, Matsuoka M (2010) TAG-1 is an inhibitor of TGFb2-induced neuronal death via amyloid b precursor protein. Biochem Biophys Res Commun 394:119–125. https://doi.org/10.1016/j.bbrc.2010.02.127. Takeda Y, Akasaka K, Lee S, Kobayashi S, Kawano H, Murayama S, Takahashi N, Hashimoto K, Kano M, Asano M, Sudo K, Iwakura Y, Watanabe K (2003) Impaired motor coordination in mice lacking neural recognition molecule NB-3 of the contactin/F3 subgroup. J Neurobiol 56:252–265. https://doi.org/10.1002/ neu.10222. Tanzi RE, Bertram L (2005) Twenty Years of the Alzheimer’s disease amyloid hypothesis: a genetic perspective. Cell 120:545–555. https://doi.org/10.1016/j.cell.2005.02.008. Taylor CJ, Ireland DR, Ballagh I, Bourne K, Marechal NM, Turner PR, Bilkey DK, Tate WP, Abraham WC (2008) Endogenous secreted amyloid precursor protein-alpha regulates hippocampal NMDA receptor function, long-term potentiation and spatial memory. Neurobiol Dis 31:250–260. https://doi.org/10.1016/j. nbd.2008.04.011. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580. https:// doi.org/10.1002/ana.410300410. Toyoshima M, Sakurai K, Shimazaki K, Takeda Y, Shimoda Y, Watanabe K (2009) Deficiency of neural recognition molecule NB2 affects the development of glutamatergic auditory pathways from the ventral cochlear nucleus to the superior olivary complex in mouse. Dev Biol 336:192–200. https://doi.org/10.1016/j. ydbio.2009.09.043. Traka M, Goutebroze L, Denisenko N, Bessa M, Nifli A, Havaki S, Iwakura Y, Fukamauchi F, Watanabe K, Soliven B, Girault J-A,

Please cite this article in press as: Bamford RA et al. The Interaction Between Contactin and Amyloid Precursor Protein and Its Role in Alzheimer’s Disease. Neuroscience (2019), https://doi.org/10.1016/j. neuroscience.2019.10.006

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R. A. Bamford et al. / Neuroscience xxx (2019) xxx–xxx

Karagogeos D (2003) Association of TAG-1 with Caspr2 is essential for the molecular organization of juxtaparanodal regions of myelinated fibers. J Cell Biol 162:1161–1172. https:// doi.org/10.1083/jcb.200305078. Truong PH, Ciccotosto GD, Cappai R (2019) Analysis of motor function in amyloid precursor-like protein 2 knockout mice: the effects of ageing and sex. Neurochem Res 44:1356–1366. https:// doi.org/10.1007/s11064-018-2669-6. Tyan SH, Shih AYJ, Walsh JJ, Maruyama H, Sarsoza F, Ku L, Eggert S, Hof PR, Koo EH, Dickstein DL (2012) Amyloid precursor protein (APP) regulates synaptic structure and function. Mol Cell Neurosci 51:43–52. https://doi.org/10.1016/j.mcn.2012.07.009. Ullrich B, Ushkaryov YA, Su¨dhof TC (1995) Cartography of neurexins: more than 1000 isoforms generated by alternative splicing and expressed in distinct subsets of neurons. Neuron 14:497–507. https://doi.org/10.1016/0896-6273(95)90306-2. Van Abel D, Michel O, Veerhuis R, Jacobs M, Van Dijk M, Oudejans CBM (2012) Direct downregulation of CNTNAP2 by STOX1A is associated with Alzheimer’s disease. J Alzheimer’s Dis 31:793–800. https://doi.org/10.3233/JAD-2012-120472. van der Kant R, Goldstein LSB (2015) Cellular functions of the amyloid precursor protein from development to dementia. Dev Cell 32:502–515. https://doi.org/10.1016/j.devcel.2015.01.022. van Dijk M, van Bezu J, Poutsma A, Veerhuis R, Rozemuller AJ, Scheper W, Blankenstein MA, Oudejans CB (2010) The preeclampsia gene STOX1 controls a conserved pathway in placenta and brain upregulated in late-onset Alzheimer’s disease. J Alzheimer’s Dis 19:673–679. https://doi.org/10.3233/JAD-20101265. Varea O, Martin-de-Saavedra MD, Kopeikina KJ, Schu¨rmann B, Fleming HJ, Fawcett-Patel JM, Bach A, Jang S, Peles E, Kim E, Penzes P (2015) Synaptic abnormalities and cytoplasmic glutamate receptor aggregates in contactin associated proteinlike 2/Caspr2 knockout neurons. Proc Natl Acad Sci USA 112:6176–6181. https://doi.org/10.1073/pnas.1423205112. Virgintino D, Ambrosini M, D’Errico P, Bertossi M, Papadaki C, Karagogeos D, Gennarini G (1999) Regional distribution and cell type-specific expression of the mouse F3 axonal glycoprotein: a developmental study. J Comp Neurol 413:357–372. Vnencak M, Paul MH, Hick M, Schwarzacher SW, Del Turco D, Mu¨ller UC, Deller T, Jedlicka P (2015) Deletion of the amyloid precursor-like protein 1 (APLP1) enhances excitatory synaptic transmission, reduces network inhibition but does not impair synaptic plasticity in the mouse dentate gyrus. J Comp Neurol 523:1717–1729. https://doi.org/10.1002/cne.23766. Voruganti VS, Nath SD, Cole SA, Thameem F, Jowett JB, Bauer R, MacCluer JW, Blangero J, Comuzzie AG, Abboud HE, Arar NH (2009) Genetics of variation in serum uric acid and cardiovascular risk factors in Mexican Americans. J Clin Endocrinol Metab 94:632–638. https://doi.org/10.1210/jc.2008-0682. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ (2002) Naturally secreted oligomers of amyloid b protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416:535–539. https://doi.org/ 10.1038/416535a. Walsh DM, Minogue AM, Sala Frigerio C, Fadeeva JV, Wasco W, Selkoe DJ (2007) The APP family of proteins: similarities and differences. Biochem Soc Trans 35:416–420. https://doi.org/ 10.1042/BST0350416. Wang Z, Wang B, Yang L, Guo Q, Aithmitti N, Songyang Z, Zheng H (2009) Presynaptic and postsynaptic interaction of the amyloid precursor protein promotes peripheral and central synaptogenesis. J Neurosci 29:10788–10801. https://doi.org/ 10.1523/JNEUROSCI.2132-09.2009. Wasco W, Bupp K, Magendantz M, Gusella JF, Tanzi RE, Solomon F (1992) Identification of a mouse brain cDNA that encodes a protein related to the Alzheimer disease-associated amyloid beta protein precursor. Proc Natl Acad Sci USA 89:10758–10762. Wasco W, Gurabhagavatula S, Paradis MD, Romano DM, Sisodia SS, Hyman BT, Neve RL, Tanzi RE (1993) Isolation and characterization of APLP2 encoding homologue of the

Alzhemier’s associated amyloid beta protein precursor. Nat Genet 5. Weichenhan D, Traut W, Go¨ngrich C, Himmelbauer H, Busch L, Monyer H, Winking H (2008) A mouse translocation associated with Caspr5-2 disruption and perinatal lethality. Mamm Genome 19:675–686. https://doi.org/10.1007/s00335-008-9148-3. Weyer SW, Zagrebelsky M, Herrmann U, Hick M, Ganss L, Gobbert J, Gruber M, Altmann C, Korte M, Deller T, Mu¨ller UC (2014) Comparative analysis of single and combined APP/APLP knockouts reveals reduced spine density in APP-KO mice that is prevented by APPsa expression. Acta Neuropathol Commun 2:36. https://doi.org/10.1186/2051-5960-2-36. Whitehouse IJ, Miners JS, Glennon EBC, Kehoe PG, Love S, Kellett KAB, Hooper NM (2013) Prion protein is decreased in Alzheimer’s brain and inversely correlates with BACE1 activity, amyloid-b levels and braak stage. PLoS One 8:1–8. https://doi.org/10.1371/ journal.pone.0059554. Wimo A, Jonsson L, Winblad B (2006) An estimate of the worldwide prevalence and direct costs of dementia in 2003. Dement Geriatr Cogn Disord 21:175–181. https://doi.org/10.1159/000090733. Wolman MA, Sittaramane V, Essner JJ, Yost HJ, Chandrasekhar A, Halloran MC (2008) Transient axonal glycoprotein-1 (TAG-1) and laminin-alpha1 regulate dynamic growth cone behaviors and initial axon direction in vivo. Neural Dev 3:6. https://doi.org/10.1186/ 1749-8104-3-6. Wu Z-Q, Li D, Huang Y, Chen X-P, Huang W, Liu C-F, Zhao H-Q, Xu R-X, Cheng M, Schachner M, Ma Q-H (2016) Caspr controls the temporal specification of neural progenitor cells through notch signaling in the developing mouse. Cerebral Cortex Cereb Cortex bhv318. https://doi.org/10.1093/cercor/bhv318. Yamamoto M, Boyer AM, Crandall JE, Edwards M, Tanaka H (1986) Distribution of stage-specific neurite-associated proteins in the developing murine nervous system recognized by a monoclonal antibody. J Neurosci 6:3576–3594. Yan R (2017) Physiological functions of the b-site amyloid precursor protein cleaving enzyme 1 and 2. Front Mol Neurosci 10. https:// doi.org/10.3389/fnmol.2017.00097. Yarchoan M, Xie SX, Kling MA, Toledo JB, Wolk DA, Lee EB, Van Deerlin V, Lee VMY, Trojanowski JQ, Arnold SE (2012) Cerebrovascular atherosclerosis correlates with Alzheimer pathology in neurodegenerative dementias. Brain 135:3749–3756. https://doi.org/10.1093/brain/aws271. Ye H, Tan YLJ, Ponniah S, Takeda Y, Wang SQ, Schachner M, Watanabe K, Pallen CJ, Xiao ZC (2008) Neural recognition molecules CHL1 and NB-3 regulate apical dendrite orientation in the neocortex via PTPa. EMBO J 27:188–200. https://doi.org/ 10.1038/sj.emboj.7601939. Yin F-T, Futagawa T, Li D, Ma Y-X, Lu M-H, Lu L, Li S, Chen Y, Cao Y-J, Yang ZZ, Oiso S, Nishida K, Kuchiiwa S, Watanabe K, Yamada K, Takeda Y, Xiao Z-C, Ma Q-H (2015) Caspr4 interaction with LNX2 modulates the proliferation and neuronal differentiation of mouse neural progenitor cells. Stem Cells Dev 24:640–652. https://doi.org/10.1089/scd.2014.0261. Yin GN, Lee HW, Cho JY, Suk K (2009) Neuronal pentraxin receptor in cerebrospinal fluid as a potential biomarker for neurodegenerative diseases. Brain Res 1265:158–170. https:// doi.org/10.1016/j.brainres.2009.01.058. Yoshihara Y, Kawasaki M, Tamada A, Nagata S, Kagamiyama H, Mori K (1995) Overlapping and differential expression of BIG-2, BIG-1, TAG-1, and F3: four members of an axon-associated cell adhesion molecule subgroup of the immunoglobulin superfamily. J Neurobiol 28:51–69. https://doi.org/10.1002/neu.480280106. Yoshihara Y, Kawasaki M, Tani A, Tamada A, Nagata S, Kagamiyama H, Mori K (1994) BIG-1: a new TAG-1/F3-related member of the immunoglobulin superfamily with neurite outgrowth-promoting activity. Neuron 13:415–426. https://doi. org/10.1016/0896-6273(94)90357-3. Young-Pearse TL, Bai J, Chang R, Zheng JB, LoTurco JJ, Selkoe DJ (2007) A critical function for -amyloid precursor protein in neuronal migration revealed by in utero RNA interference. J Neurosci

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27:14459–14469. https://doi.org/10.1523/JNEUROSCI.470107.2007. Young-Pearse TL, Chen AC, Chang R, Marquez C, Selkoe DJ (2008) Secreted APP regulates the function of full-length APP in neurite outgrowth through interaction with integrin beta1. Neural Dev 3:15. https://doi.org/10.1186/1749-8104-3-15. Zeng Y, Liu J-X, Yan Z-P, Yao X-H, Liu X-H (2015) Potential microRNA biomarkers for acute ischemic stroke. Int J Mol Med 36:1639–1647. https://doi.org/10.3892/ijmm.2015.2367. Zhang X, Herrmann U, Weyer SW, Both M, Mu¨ller UC, Korte M, Draguhn A (2013) Hippocampal network oscillations in APP/ APLP2-deficient mice. PLoS One 8. https://doi.org/10.1371/ journal.pone.0061198 e61198. Zhou L, Bara˜o S, Laga M, Bockstael K, Borgers M, Gijsen H, Annaert W, Moechars D, Mercken M, Gevaer K, De Strooper B (2012) The neural cell adhesion molecules L1 and CHL1 are cleaved by

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BACE1 protease in vivo. J Biol Chem 287:25927–25940. https:// doi.org/10.1074/jbc.M112.377465. Zou Y, Zhang WF, Liu HY, Li X, Zhang X, Ma XF, Sun Y, Jiang SY, Ma QH, Xu DE (2017) Structure and function of the contactinassociated protein family in myelinated axons and their relationship with nerve diseases. Neural Regen Res 12:1551–1558. https://doi.org/10.4103/1673-5374.215268. Zuko A, Bouyain S, Van Der Zwaag B, Burbach JPH (2011) Contactins: Structural aspects in relation to developmental functions in brain disease. Adv Protein Chem Struct Biol. https:// doi.org/10.1016/B978-0-12-386483-3.00001-X. Zuko A, Oguro-Ando A, Post H, Taggenbrock RLRE, van Dijk RE, Altelaar AFM, Heck AJR, Petrenko AG, van der Zwaag B, Shimoda Y, Pasterkamp RJ, Burbach JPH (2016) Association of cell adhesion molecules contactin-6 and latrophilin-1 regulates neuronal apoptosis. Front Mol Neurosci 9:1–16. https://doi.org/ 10.3389/fnmol.2016.00143.

(Received 25 July 2019, Accepted 3 October 2019) (Available online xxxx)

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