Peptides isolated from animal venom as a platform for new therapeutics for the treatment of Alzheimer's disease

Accepted Manuscript Peptides isolated from animal venom as a platform for new therapeutics for the treatment of Alzheimer's disease

L.C. Camargo, G.A.A. Campos, P.R. Galante, A.M. Biolchi, J.C. Gonçalves, K.S. Lopes, M.R. Mortari PII: DOI: Reference:

S0143-4179(17)30218-4 doi:10.1016/j.npep.2017.11.010 YNPEP 1839

To appear in:

Neuropeptides

Received date: Revised date: Accepted date:

3 August 2017 9 November 2017 23 November 2017

Please cite this article as: L.C. Camargo, G.A.A. Campos, P.R. Galante, A.M. Biolchi, J.C. Gonçalves, K.S. Lopes, M.R. Mortari , Peptides isolated from animal venom as a platform for new therapeutics for the treatment of Alzheimer's disease. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Ynpep(2017), doi:10.1016/j.npep.2017.11.010

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Title: Peptides isolated from animal venom as a platform for new therapeutics for the treatment of Alzheimer`s Disease

Authors:

Luana Cristina Camargo: [email protected]

PT

Camargo LC, Campos GAA, Galante PR, Biolchi AM, Gonçalves JC, Lopes KS, Mortari MR*

SC

Priscilla Galante Ribeiro: [email protected]

RI

Gabriel Avohay Alves Campos: [email protected]

Andreia Biolchi Mayer: [email protected]

NU

Jacqueline Coimbra Gonçalves: [email protected] Kamila Soares Lopes: [email protected]

MA

Affiliation of all authors:

Corresponding address:

ED

Laboratory of Neuropharmacology, Department of Physiological Sciences, Institute of Biological Sciences, University of Brasília, Brasília, Brazil.

EP T

Laboratory of Neuropharmacology, Department of Physiological Sciences, Institute of Biological Sciences, University of Brasília, Brasília-DF, 70910-900, Brazil.

AC C

Phone: +55-61-3107-3123; Fax: +55-61-3107-2904.

*Corresponding author: Márcia Renata Mortari: [email protected]

ACCEPTED MANUSCRIPT ABSTRACT Alzheimer’s Disease (AD) is a progressive neurodegenerative disease that deeply affects patients, their family and society. Although scientists have made intense efforts in seeking the cure for AD, no drug available today is able to stop AD progression. In this context, compounds isolated from animal venom

PT

are potentially successful drugs for neuroprotection, since they selectively bind

RI

to nervous system targets. In this review, we presented different studies using

field

that

will

be

very

helpful

in

SC

peptides isolated from animal venom for the treatment of AD. This is a growing understanding

even

curing

KEYWORDS:

MA

NU

neurodegenerative diseases, especially AD.

and

Alzheimer’s

AC C

EP T

ED

neuroprotection; treatment.

disease;

memory;

peptides;

venom;

ACCEPTED MANUSCRIPT HIGHLIGHTS AD is the most common neurodegenerative disease in the world;



AD is inexorable and progressive;



No drug approved today can cure or prevent AD;



Animal toxins are selective for targets in the nervous system of

PT



mammals;

RI

Peptides isolated from animal venom could cure or clarify the molecular

EP T

ED

MA

NU

SC

mechanism of AD.

AC C



ACCEPTED MANUSCRIPT 1. INTRODUCTION Alzheimer’s disease (AD) is the most common form of dementia among adults. Learning and memory impairments occur due to progressive synaptic loss, as well as neuronal death. Alois Alzheimer described neuritic plaques and neurofibrillary tangles in a post-mortem patient’s brain for the first time in 1906.

PT

Since then, many studies have demonstrated that those protein aggregations

RI

are responsible for the neurodegeneration in AD (Goedert and Spillantini,

SC

2006).

According to the latest World Alzheimer Report (2015), the world’s elderly

NU

(over 60) population is increasing; therefore, the prevalence of chronic

MA

diseases, especially dementia, also accompanies this increase. Nowadays, 46.8 million (2015) people have dementia, and projections demonstrate that this

ED

population will increase 60% (74.7 million) and 181% (131.5 million) worldwide, from 2015-2030 and 2015-2050, respectively. In addition, the incidence of

EP T

dementia increases through the years passed. At 60-64 years old, the incidence is 3 per 1000 people, increasing to 175 per 1000 in people over 95 years old

AC C

(Prince et al., 2015).

The diagnosis of AD is only confirmed post-mortem, although some modern techniques like MRI, PET-scan of amyloid-β and PET-FDG can correlate the pathognomonic alterations with AD diagnosis. Three stages are considered in AD: Pre-clinical, Mild Cognitive Impairment (MCI) and Dementia stages. (Hyman et al., 2012). The pre-clinical stage is characterized by the initial presence of neuritic plaques and neurofibrillary tangles but with a lack of clinical signs. This stage

ACCEPTED MANUSCRIPT demonstrates that AD begins its development years before the first symptoms. Therefore, the improvement of the techniques mentioned above is essential for detecting this stage (Blennow et al., 2015; Sperling et al., 2011). A recent study was able to correlate neuritic plaque load with cognition impairment in AD patients (Donohue et al., 2017). MCI is the first stage at which initial signs can

PT

be diagnosed, such as episodic memory lapses (Selkoe, 2003). This stage is

RI

very useful for the diagnosis of AD (Petersen, 2011; Petersen et al., 2009). The

SC

last stage is dementia, in which there is a progressive and inexorable cognition loss; also, there is non-cognitive loss, such as emotional alterations. The

NU

disease progresses with motor deficits until the patient is completely dependent and needs constant care. According to medical reports, since AD induces

MA

morbidity, including swallowing impairment, weight loss and the decrease of immune functions, the patient usually dies from respiratory dysfunction,

ED

especially bronchopneumonia due to infections (Brunnström and Englund, 2009). Also, in comparison with other conditions, elderly people with AD die

EP T

earlier than elderly people without AD, so the disease causes death as well (Alzheimer’s Association, 2014).

AC C

1. ANIMAL VENOM PEPTIDES Animal venoms are considered good candidates for new drug development in neurodegenerative diseases. Venom compounds were selected to be very specific to their targets through the time course of evolution (Monge-Fuentes et al., 2015; Silva et al., 2015). In this review, we consider some peptides isolated from animal venom, which could be potential drugs for AD (Barage and Sonawane, 2015), considering different alterations that are seen in AD patients (Table 1).

ACCEPTED MANUSCRIPT 1.1. Amyloid-β hypothesis and Snake venom peptide In 2016, the amyloid hypothesis celebrated 25 years (Selkoe and Hardy, 2016a). Neuritic plaques are aggregates of β-amyloid protein oligomers. The APP (amyloid protein precursor) is part of the type-I single-pass transmembrane

PT

protein family and has distinct roles in the brain during the course of life (Simons et al., 1996). Even though a single gene codes the APP, three isoforms

RI

have been identified: APP695 (expressed in neurons), APP751 and APP770

SC

(fibroblast and peripheral tissues). Mutations in this gene modify the cleavage of the APP by secretases, which can lead to the formation of b-amyloid monomers

NU

(Cacace et al., 2016). The structure is made of short cytoplasmatic and long

MA

extracellular domains. APP functions depend on the interactions between other APPs, i.e. the formation of trans dimers has a role in cell-cell adhesion, synaptic proteins and N-methyl-D-aspartate (NMDA) receptors (see Review: (Müller et γ- and β-secretases are the enzymes responsible for the formation

ED

al., 2017).

EP T

of β-amyloid monomers from APP (Hardy and Higgins, 1992). The β-secretases cleave APP in the extracellular domain, and γ-secretase cleaves in the

AC C

transmembrane domain in distinct positions that produce monomers with different lengths (Esler and Wolfe, 2001). Classically, two isoforms are the most studied, Aβ-40 and Aβ-42; these are the most abundant and the most toxic isoforms, respectively (Nussbaum and Ellis, 2003). The neuritic plaques are an aggregation of Aβ oligomers. The peptide Aβ monomers shift their conformation from random coil to β- sheet secondary structure, and they are able to interact among themselves to form fibrils (for review (Qiu et al., 2015)). These fibrils are formed due to the amino acid charge of the Ab peptide, since the positively charged amino acid helps the

ACCEPTED MANUSCRIPT β-sheet formation, and the negative charge stabilizes these structures (Mishra et al., 2015; Tofoleanu and Buchete, 2012). A recent study demonstrated that, contrary to initial belief, the oligomers are more toxic than the plaques (Walsh and Selkoe, 2004). It seems that a

PT

dynamic equilibrium between toxic oligomers and fibrils is responsible for synaptic dystrophy and neuronal death rather than only one form (Pike et al.,

RI

1993; Walsh and Selkoe, 2004). These oligomers impair synaptic activity and

SC

long-term potentiation, and cause cognitive and memory impairment in rodent models (Benilova et al., 2012) through a different mechanism, i.e. pore

NU

formation in the membrane (Gunn et al., 2016). Besides, oligomers have

MA

greater diffusion rates and exposed hydrophobic amino acids, which helps them to pass through and insert themselves in the neuron membrane (Tofoleanu and Buchete, 2012). Neuritic plaques seem to have a physical limit to their load of

ED

Aβ oligomers, so the excess oligomers become free and are able to interact

EP T

with the synaptic membrane. A study reported that patients with a high level of Aβ plaques but low levels of oligomers had no cognitive deficits, unlike patients

AC C

with cognitive impairment, who had high levels of oligomers (Esparza et al., 2013)(Selkoe and Hardy, 2016b). Therefore, it is believed that Aβ oligomers are responsible for synaptic impairment and Aβ plaques induce neurodegeneration by activation of microglia (Haass and Selkoe, 2007; Walsh and Selkoe, 2004). All in all, Aβ alters neuronal homeostasis by deregulating calcium entry, which will activate kinases. These kinases can hyperphosphorylate the Tau protein, forming neurofibrillary tangles, and activate the apoptosis pathway

ACCEPTED MANUSCRIPT (Hardy and Higgins, 1992). In addition, they can induce lipid and protein oxidation, activating apoptosis. In this context, components of snake venom have played an important role as markers for AD. An example is activation factor V, initially observed during the investigation of the proteolytic activity of the venom from Daboia

and

Bhattacharyya (2013) (Bhattacharjee and

RI

al., 1996). Bhattacharjee

PT

russelli russelli, a subspecies of Russell's viper found in eastern India (Tsai et

SC

Bhattacharyya, 2013) perceived that the venom of this species contains specific proteins derived from RVV-V peptides that cleave and disrupt the preformed

NU

Aβ-amyloid fibrils, as well as the protection of human neuronal cells from cells with Aβ-amyloid induced cytotoxicity. Therefore, peptides isolated initially from

MA

venom of other species, such as Russell’s Viper, offer an encouraging

for the treatment of AD.

EP T

1.2. Tauopathy

ED

opportunity for the treatment of amyloidoses and may provide vital information

Tau is a microtubule-associated protein in axons of neurons. This protein

AC C

promotes microtubule assembly during neurite extension (Drubin et al., 1988; Weingarten

et

al.,

1975).

Under

pathological

conditions,

Tau

is

hyperphosforylated, relocates to the somatodendritic region and aggregates in paired helical filaments called neurofibrillary tangles (NFT) (Binder et al., 1985; Braak et al., 1994; Wischik et al., 1988). The increase in Tau enhances a failure of energy generation and glucose metabolism due to the impairment of mitochondria and Endoplasmatic Reticulum transport inside the neuron, thus leading to neuronal loss (Ebneth et al., 1998)

ACCEPTED MANUSCRIPT According to the stages described by Braak and Braak (1995), NFT begins to appear in the entorhinal cortex, especially in layers II and III. Interestingly, NFT accumulation is correlated to signs of AD progression, so can be used to classify the severity of AD lesions. In stages I and II, there is diffuse NFT and no clinical signs. In stages III and IV, changes in the hippocampus and

PT

dystrophy of both the entorhinal and paraentorhinal cortex coincide with initial

RI

cognitive deficits and personality changes. During the last stages (V and VI),

SC

NFT is found in all areas of the brain cortex, and there is massive neuronal loss in the associative cortex (Braak and Braak, 1995).

NU

In contrast with the amyloid hypothesis, the treatment of Taupathy as a possible mechanism to cure AD has been only recently discussed. New

MA

compounds are tested to prevent or revert the misfolded Tau protein, although there are no recent data about the use of peptides isolated from animals that

ED

would bind to tau protein and prevent AD (Cantwell et al., 2007; Šimić et al.,

EP T

2016).

1.3. Neuroinflammation and Scorpion Venom Peptide

AC C

Neurite plaques are Aβ aggregation surrounded by reactive microglia. Microglia are the defense cells resident in the brain. When pathogens or damage occurs, microglia change to a M1 phenotype, which produces proinflammatory chemokines until the pathogen is eliminated. Aβ induces this phenotype, but the reactive microglia are unable to phagocytize and destroy the plaques, considering that Aβ fibrils are resistant to enzymatic degradation, enhancing damage caused by neuroinflammation. Among the pro-inflammatory molecules, interleukin 12 (IL-12), 23 (IL-23) and 1β (IL-1β) have increased

ACCEPTED MANUSCRIPT levels in AD patients (Heneka et al., 2015; Vom Berg et al., 2012). Besides, IL1β helps to regulate APP processing, which produces Aβ peptides (Akama and Van Eldik, 2000). These molecules activate caspases 1, 3/7 and 8 (Fricker et al., 2013), NLRP3 inflammasome (Halle et al., 2008), and these

mediators

PT

produce even more neurotoxic molecules (Heneka et al., 2015). Two mutations have been identified as AD risks: the triggering receptor in

RI

myeloid cells 2 (TREM2) (Kober et al., 2016) and the myeloid cell surface

SC

antigen (CD33) (Griciuc et al., 2013). These receptors are involved in phagocytosis, and mutations in these genes alter the phagocytic ability of

NU

microglia (Griciuc et al., 2013; Hsieh et al., 2009). Aβ is recognized by toll-like

MA

receptors (TLR), and others (Stewart et al., 2010). Depending on the receptor binding, different pro-inflammatory molecules are produced (Bamberger et al.,

ED

2003; Heneka et al., 2015; Liu et al., 2005). Astrocytes are very important for neuronal survival and synaptic

EP T

clearance. In the case of pathogens, astrocytes can also become reactive in response to damage (Medeiros and LaFerla, 2013). APOE is released by

AC C

astrocytes to help Aβ clearance by microglia (Castellano et al., 2011). Another well-known mutation of AD is in the APOE gene (Corder et al., 1993). A heat resistant peptide (SVHRP) isolated from the venom of the scorpion Buthus martensii Karsch has neuroprotective effects and induces neurogenesis and neuronal maturation, which could prevent neurodegeneration in AD. The SVHRP induces astrocyte activity, which up regulates the BrainDelivery Neurotrophic factor (BDNF) and can cause maturation of stem cells in the brain after an injury, producing new neurons (Wang et al., 2014). In a

ACCEPTED MANUSCRIPT transgenic model of AD in the worm Caenorhabditis elegans expressing Aβ-42, the SVHRP was able to ameliorate paralysis induced by the Aβ-42 peptide. In addition, there was a reduction in Aβ oligomers and superoxide production, which decreases oxidative stress, when treated with SVHRP (X. Zhang et al.,

PT

2016). 1.4. Exenatide and Glucose metabolism impairment in AD

RI

Over recent decades, emerging evidence has given support to the theory

considering AD

as

a type

of

brain-related diabetes

or

type

III

NU

start

SC

that AD may be linked to brain insulin resistance, leading some authors to even

diabetes (Monte and Wands, 2008; Steen et al., 2005). One of the first

MA

indications was the positive association between dementia and diabetes mellitus (Ott et al., 1996), with an almost two-fold risk of dementia in diabetic showed similar results,

ED

patients (Ott et al., 1999). Several other studies

reinforcing the higher risk of AD in type II diabetes (Gudala et al., 2013) and

EP T

also associating poor glycemic control (Tuligenga et al., 2014) and obesity (Profenno et al., 2010) to faster cognitive decline and AD. Finally, post mortem revealed

that

the

brain

of

AD

patients

showed

defective

AC C

studies

insulin signaling and lower responsiveness to insulin compared to healthy subjects (Talbot et al., 2012). Although the brain was initially considered to be unaffected by insulin, several brain regions present insulin receptors (IR), especially the olfactory bulb, the cortex and the hippocampus (Marks et al., 1990). Moreover, the insulin signaling pathway influences a myriad of essential processes that are defective in

AD,

regulating,

for

example, memory formation and

consolidation,

ACCEPTED MANUSCRIPT inflammatory processes and synaptic plasticity (Blázquez et al., 2014; Duarte et al., 2012). Further knowledge about the insulin pathway is also important in understanding its role in AD. The IR is a tyrosine kinase receptor that, when activated, recruits and phosphorylates a family of proteins named insulin

PT

receptor substrates (IRS), which, in turn, activate downstream proteins

RI

responsible for various insulin actions (White, 2004). While phosphorylation of

SC

IRS at tyrosine residues results in its activation, the phosphorylation at serine residues is responsible for the inactivation of IRS. JNK is one of the

NU

proteins capable of inactivating IRS, and post mortem studies reveal that AD patients present high levels of inactivated IRS-1 (Yarchoan et al., 2015),

MA

possibly by excessive Aβ-induced expression of TNF-a leading to enhanced inactivation of IRS through JNK (Bomfim et al., 2012). Moreover, Aβ oligomers

ED

are not only associated with reduced IR responsiveness but insulin pathway

EP T

impairment can also lead to higher production of Aβ, possibly resulting in a vicious neurodegenerative cycle (Zhao et al., 2009). Taken together, evidence of insulin resistance in AD not only contributes

AC C

to the understanding of AD-associated pathology but also introduces a new and promising alternative for more effective treatments (Baglietto-vargas et al., 2016). In this context, several animal studies demonstrated the effectiveness of insulin pathway activation in protecting neurons from Aβ-induced degeneration, improvement of memory and cognition (Chen et al., 2016). More recently, researchers demonstrated the ability of intranasal insulin to improve memory and cognition in patients with Mild Cognitive Impairment and moderate AD

ACCEPTED MANUSCRIPT (Craft et al., 2017), reinforcing the important role of insulin modulation as a therapy in AD. Exenatide is the synthetic version of the peptide Exendin-4, a 39 aminoacid peptide isolated from the saliva of the American lizard Haloderma suspectum or Gila monster. Exenatide has a 53% similarity with glucagon-like 1

(GLP-1) and

revealed

itself as

a

potent GLP-1 receptor

PT

peptide

RI

agonist (Raufman et al., 1992). GLP-1 is an endocrine hormone from the

SC

incretin family that is released as a response to food ingestion and is responsible for important actions such as insulin release by pancreatic beta

NU

cells and lowering glucagon release, a profile with the potential to compensate for the peripheral insulin resistance associated with type 2 diabetes (T2D)

MA

(Drucker and Nauck, 2006). In this context, Exenatide demonstrated efficacy as adjuvant treatment in controlling hyperglycemia in T2D patients, resulting in

ED

FDA approval of Exenatide as a commercial T2D treatment in 2005 (Davidson et al., 2005). The main advantages of Exenatide are its tolerability, its ability to

EP T

cross the blood-brain barrier and its longer plasmatic life when compared to GLP-1, although treatment requires twice-daily subcutaneous administrations.

AC C

While Exenatide may be considered a fairly established treatment for T2D, novel applications are emerging in the neurodegenerative disorders field. Animal studies revealed that GLP1-R is expressed in CNS neurons, and GLP-1 agonists promote neuroprotection and neurogenesis, compensate brain insulin resistance

and

can reduce memory impairment and enhance learning

(Tramutola et al., 2016). Moreover, Exenatide administration was able to prevent JNK-mediated IRS phosphorylation and improved memory in an animal model of AD (Bomfim et al., 2012). Promising evidence also arose from an

ACCEPTED MANUSCRIPT open-label clinical trial wherein 20 PD patients treated with Exenatide for 12 months presented a significant improvement that persisted for 12 more months after treatment termination (Aviles-olmos et al., 2014), indicating a potentially neuroprotective activity. For these reasons, GPL-1R modulation by Exenatide has been suggested as a promising approach for the treatment of AD (Appleby

PT

and Cummings, 2013; Holscher, 2010). In this context, a phase II clinical trial

RI

assessing Exenatide efficacy in MCI and early AD patients has been completed

SC

(NCT01255163), and a phase III clinical trial evaluating Exenatide treatment in

NU

MCI patients is currently recruiting (NCT02847403).

1.5. Cholinergic hypothesis in AD and Peptides isolated from Snake venom

MA

Cholinergic neurons are essential for memory formation and learning (Perry et al., 1999). Disruption in this circuit has been found in the brains of AD

ED

patients. Choline acetyltransferase (ChAT) and acetylcholine synthesis are also

EP T

reduced. The nucleus basalis of Meynert is the main area for input to the cortex, and it is mainly made up of cholinergic neurons. In AD, those neurons are severely damaged (Bartus et al., 1982). Nowadays, it is very clear that the

AC C

cholinergic system is impaired in AD, and increases cognitive deficits (for review: (Terry and Buccafusco, 2003)). Therefore, a mouse model of AD was developed by using streptomycin, which disrupts cholinergic synapses (Winslow and Camacho, 1995). As a result of the above research, three acetylcholinesterase inhibitors have been approved for mild to moderate AD. Tancrine was discontinued due to its side effects (Klafki et al., 2006). Donepezil, Galantamine and Risvatigmine are used to improve symptoms of impairment in cognition and non-cognition in

ACCEPTED MANUSCRIPT AD patients by inhibiting AChE activity and decreasing formation of AChE and the Aβ complex. Donepezil and Galantamine are reversible selective drugs for AChE, and Rivastigmine is semi-reversible; it also binds to butirilcholinesterase (BChT), which might improve the treatment since BChT presents increased levels in the brain of AD patients. BChT affects the formation of neuritic

PT

plaques. Moreover, Donepezil also binds to nicotinic receptors and Galantamine

RI

is able to reduce Aβ levels (Parsons et al., 2013).

SC

Other cholinergic drugs have demonstrated promising results for AD treatment. Muscarinic agonists were able to activate PKC, which induces the

NU

activation of other kinases. These, in turn, activate α-secretase then alter APP

MA

processing and decrease Aβ peptide formation (Gu et al., 2003; Haring et al., 1998; Lin et al., 1999). On the other hand, muscarinic activation of PKC inhibits the GSK-3β pathway and decreases hyperphosphorylation of TAU (Lahmy et

ED

al., 2013). In addition, the nicotinic agonists have a neuroprotective effect

EP T

because they attenuate Aβ toxicity (Liu et al., 2001; Woodruff‐Pak et al., 2002). Neurotoxins, such as dendrotoxins, muscarinic toxins and fasciculin (FAS),

AC C

are the main toxins isolated from snake venom peptides that have relevant action in the Central Nervous System. Fasciculin toxin (FAS), which represents a family of peptides (FAS-I, FAS-II, and FAS-III), was isolated from the venom of the Eastern Green Mamba, Dendroaspis angusticeps (Rodríguez-Ithurralde et al., 1983). This peptide family is extremely selective, exhibiting a powerful reversible inhibitory function of the enzyme acetylcholinesterase (AChE) (Harel et al., 1995). Some studies that evaluated the interaction of toxins extracted from snake venom with the

ACCEPTED MANUSCRIPT AChE enzyme have been ratified by in silico interaction and binding tests with their receptors in structural models. As a result, the crucial role of some proteins and receptors involved in AD has been elucidated (Waqar and Batool, 2015). The α-Neurotoxins (ATX) were first isolated from the Taiwan banded krait (Bungarus Multicinctus) and, years later, were found in the venom of other

PT

species of snakes. The α-Neurotoxins are divided into two amino acid chain

RI

length subtypes, such as Atraxin (ATX) with 61 amino acid residues

SC

corresponding to the short chain compounds, and α-bungarotoxin (BTX) with 74 amino acid residues, which was classified as a long chain peptide (Samson et

NU

al., 2002). This particular action is due to a competitive inhibition of acetylcholine (ACh) binding to its receptors, preventing depolarization in

MA

postsynaptic membranes, as well as blocking neuromuscular transmission (Samson et al., 2002; Tsetlin, 2014). As a result of sequence-based binding

ED

mechanism templates, an important similarity was observed between the

EP T

sequences and the structure of the proteins (Aβ-42) and the ATX extracted from the venom of snakes in the blockage of the AChR channel opening (Maatuk and Samson, 2013). Therefore, these studies contribute to the initial knowledge of

AC C

neurotoxicity and impairment of cognition, which could support the identification of pathogenic processes of Alzheimer's disease. Interestingly, another class of neurotoxins, but with different action from ATX, is the Dendrotoxins. Dendrotoxin 7, Dendrotoxin 7 and Dendrotoxin K (Dufton and Harvey, 1998) were extracted from the venom of the Mamba snake (Dendroaspis). They act by blocking specific subtypes of potassium channels present in neurons, which increases the release of the neurotransmitter acetylcholine in the synaptic cleft (Harvey and Karlsson, 1984; Harvey and

ACCEPTED MANUSCRIPT Robertson, 2004). The interaction of these classes of dendrotoxins with the AChE enzyme was similar to that of the FAZ toxin, as seen in molecular docking studies that identified the binding of amino acid residues of these toxins and their interaction with the enzyme AChE, which highlights their therapeutic potential for treatment of AD (Waqar and Batool, 2015).

PT

In the same species in 1998, Adem and co-workers isolated two MT1

RI

and MT2 proteins from Mamba, Dendroaspis angusticeps, which they called

SC

muscarinic toxins (MT). Two muscarinic toxins (MT1) and (MT2) were able to inhibit the binding of the 3H-QNB muscarinic antagonist on synaptosomal

NU

membranes of rat cortex. The displacement of the radioligand was partial, which demonstrated the specificity of these toxins to only a few subtypes of

MA

muscarinic receptors. Later, other proteins with muscarinic actions were isolated and named MT3, MT4, MT7 and Isotoxin of M1-toxin (Carsi and Potter,

ED

2000; Ducancel et al., 1991). Muscarinic receptors are involved in memory

EP T

consolidation; they are also relevant tools for elucidating molecules with affinity to these receptors (Jerusalinsky et al., 1993). The peptide called Muscarinic Toxin 2 (MTX2) played an agonist-like role in the inhibitory avoidance learning

AC C

task following intra-hippocampal injection of MTX2 in Wistar rats. This peptide was able to cause a dose-dependent retrograde memory facilitation, with the highest dose of 1.5 μg causing a maximum step-down facilitation, which can be suppressed with the infusion of scopolamine, a muscarinic receptor antagonist (Jerusalinsky et al., 1993). 1.6. Glutamatergic hypothesis in AD and Conantoxin-G As in other neurodegenerative diseases, glutamatergic excitotoxicity plays an important role in neuronal death in AD (Olney and Sharpe, 1969).

ACCEPTED MANUSCRIPT When exacerbated glutamate, the most common excitatory neurotransmitter, is released on the synaptic cleft its receptors are over activated (Chen et al., 2000). In the case of NMDA receptors, this over-activation leads to an increase in the time that the channel remains open, causing the flow of more ions.

PT

Among those ions, calcium is the most critical when it enters the cell due to its

RI

role in cellular signaling (for review: (Mehta et al., 2013)). Calcium modulates

SC

calcium/calmodulin-dependent protein kinase II (CAMKII), which activates protein kinase C (PKC) and A (PKA). These kinases then activate cAMP

NU

response elements binding protein (CREB). CREB is the transcription factor responsible for transcription of the membrane receptor in the post-synaptic

MA

membrane. These pathways are one of the most common for the physiological mechanism of memory and learning, which is called Long Term Potentiation

ED

(LTP) (Kamat et al., 2016; Wang et al., 2004).

EP T

In AD, Aβ-oligomers, especially dimers and trimers, alter glutamate reuptake through EAAT blocking, increasing glutamate binding in the NMDA consequently

AC C

receptor,

causing

synaptic

disruption.

Blocking

glutamate

reuptake would impair GABA production, generating unbalance between both neurotransmissions, which contributes to synaptic impairment (Lei et al., 2016). Besides,

many

studies

have

demonstrated

that Aβ injection induces

hyperexcitability in hippocampus cell in different models (Busche et al., 2012; Minkeviciene et al., 2009; Ren et al., 2014) Aβ accumulation activates the GluN2B subunit in the NMDA receptors (Ferreira et al., 2012). Additionally, activation of NMDA receptors increases β-

ACCEPTED MANUSCRIPT secretase activity compared to α-secretase, inducing Aβ overproduction (Y. Zhang et al., 2016). This overactivation of NMDAR can also induce TAU hyperphosphorylation (Mondragón-Rodríguez et al., 2012). Another receptor affected by Aβ accumulation is AMPAR. Aβ activates PKA phosphorylation of the GLU1A subunit and expression of calcium-permeable AMPAR (Megill et al.,

PT

2015; Whitehead et al., 2017), which is consistent with increased CP-AMPAR in

RI

AD patients (Marcello et al., 2012). These receptors also increase calcium

SC

influx, disrupting synapses and inducing neurodegeneration (LaFerla, 2002). Memantine is a NMDAR blocker approved for the treatment of moderate-

NU

severe AD. This drug is considered neuroprotective due to its ability to prevent

MA

calcium influx under pathological conditions, and to avoid neuronal loss. Unfortunately, memantine was not able to abolish AD progress (Reisberg et al.,

ED

2003).

The marine environment emerges as one of the potential sources of

EP T

neuroactive compounds for the treatment of Alzheimer's. In this field, the conantokin peptides, a family of molecules extracted from the predatory marine

AC C

snail of the Conus genus, are able to specifically antagonize the NMDA receptor (Prorok and Castellino, 2007). This is one of the targets that may be responsible for mediating neurotoxicity in the physiopathology of AD (Dodd et al., 1994). Ragnarsson and co-workers (2002) (Ragnarsson et al., 2002) observed that the synthetic analogues of Conantoxin-G (con-G), a molecule originally isolated from the venom of Conus geographus, may be useful as an antiexcitotoxic agent to treat this neurological disease. In their study, they observed the activity of two analogues, Ala(7)– and Lys(7)–con-G, in relation to their displacement of spermine-enhanced [3H]MK-801 binding to different brain regions, both in

ACCEPTED MANUSCRIPT control and AD cases. As a result, it was demonstrated that Ala(7)–con-G was more potent than Lys(7)–con-G, although Lys(7)–con-G had a lower value of IC 50 in AD cases than in controls. Besides that, both peptides are able to cause inhibition of spermine-enhanced [3H]MK-801 binding in all brain areas analyzed, at a rate of 100%. Peptides isolated from arthropods and memory improvement venom

has

generated

great

expectations

in

the

RI

Arthropod

PT

3.3.

SC

pharmacological industry, especially in neurological diseases such as epilepsy, stroke, Parkinson and Alzheimer (Silva et al., 2015). The venom has many

NU

components like proteins, biogenic amines and peptides. These deserve special attention because of their high specificity and low toxicity. Peptide-based drugs

MA

are growing on the pharmacological market, with 150 new drugs in clinical trials (Danho et al., 2009; Estrada et al., 2007; Lien and Lowman, 2003).

ED

For example, the toxin Tx3-1 from spider Phoneutria nigriventer is a

EP T

selective blocker of transient outward K+ currents (IA ). The IA current, among other functions, is responsible for the setting of the LTP threshold (Chen et al., 2006). In AD, the Aβ peptide regulates this current and the potassium channels

AC C

that produce this current increase in cells treated with the Aβ peptide (Plant et al., 2006). Therefore, blocking the IA current would improve memory and could be a good treatment for AD signs. This peptide demonstrated effectiveness in improving the memory of animals tested in an assay involving a novel object recognition task, positively enhancing both short- and long-term memory and without generating adverse effects. It was also able to repair the damage in memory generated by aggregation of Aβ-25-35 (Gomes et al., 2013).

ACCEPTED MANUSCRIPT Another interesting toxin is apamin, an octadecapeptide originally found in the venom of the honey bee Apis millifera and characterized as the smallest neurotoxin able to cross the blood-brain barrier. This molecule has numerous binding sites in various brain areas involved with learning and memory processing, such as hippocampal formation and cingulate cortex (Mourre et al.,

PT

1987, 1986). In 1991, Messier and co-workers (Messier et al., 1991) examined

bar-pressing

administrations.

response

in mice, after pre- and post-training

SC

motivated

RI

if apamin had any effect on the acquisition and the retention of an appetite-

As results, they verified that apamin may act in physiologic

NU

mechanisms that modulate memory, since post-training was able to facilitate memory retro-actively and non-contingently, in order to make it easier for

MA

memory processes to take place shortly after training with a novel task. Another study elucidated that apamin can enhance memory in the Morris Water Maze

ED

and Passive avoidance test in mice (Staay et al., 1999). It was demonstrated in another study that this molecule can have a potential for use in AD and the

EP T

normal aging process, because its chronic administration in rats was able to increment the spine density and dendritic length, mainly in the hippocampal

AC C

formation, a limbic structure important for cognition-related processes ( ROMERO-CURIEL et al., 2011). This work also suggested that apamin may act in the regulation of glutamatergic excitability because it causes modulation in the

small

conductance

calcium-activated

K+

channels

(SK

channels).

Furthermore, Levin et al. (2010) (Levin et al., 2010) suggested that posthypoxic hyperexcitability in the hippocampal CA1 pyramidal neurons is inhibited in vitro by apamin.

ACCEPTED MANUSCRIPT Another hymenopteran animal produced a peptide that could be useful for the treatment or study of AD. Mastoparan-7, a polyfunctional peptide isolated from wasp venom, induces synaptic plasticity, increasing dendritic spine formation in hippocampal neurons by the activation of Gα0 protein (Ramírez et al., 2015). One of the AD hypotheses is the accumulation of Aβ

PT

peptides in hippocampal and frontal cortex synapses (Hardy and Selkoe, 2002),

RI

so that increasing dendritic spine density in these areas could be a way to

Peptides

are

SC

improve memory in patients. abundant compounds

in animal venom, and their

NU

application as drugs for treating a large number of diseases has been used for many years. Those compounds are promising, especially due to their specificity

MA

to nervous system targets, such as receptors, neurotransmitters, and the ion

4. CONCLUSION

ED

channel.

EP T

This review brings new findings about possible treatments of AD using peptides isolated from animal venom. Although only a few peptides have been

AC C

tested and there is only initial knowledge regarding the use of those peptides in AD treatment, it seems that this field will increase in the future. Peptides isolated from venom have already been tested for many neurological diseases like Parkinson’s disease, epilepsy and chronic pain. There is increasing evidence that these peptides are promising drugs for neurodegenerative diseases, and more findings are expected in the near future.

ACCEPTED MANUSCRIPT

ACKNOWLEDGMENTS This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq [grant numbers 444292/2014-4], Fundação de Empreendimentos Científicos e Tecnológicos – FINATEC and Fundação de à

Pesquisa

do

Distrito

Federal

-

FAPDF

(grant

number

PT

Apoio

0193.000494/2015). The authors LCC, KSL and JCG received fellowships from

and

ABM

received

fellowships

from

EP T

ED

MA

NU

Desenvolvimento Científico e Tecnológico – CNPq.

AC C

Conselho

SC

GAAC

RI

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES. Nacional

de

ACCEPTED MANUSCRIPT REFERENCES Akama, K.T., Van Eldik, L.J., 2000. β-Amyloid stimulation of inducible nitric-oxide synthase in astrocytes is interleukin-1β-and tumor necrosis factor-α (TNFα)-dependent, and involves a TNFα receptor-associated factor-and NFκB-inducing kinase-dependent signaling mechanism. J. Biol. Chem. 275, 7918–7924. Appleby, B.S., Cummings, J.L., 2013. Discovering New Treatments for Alzheimer â€TM s Disease by Repurposing Approved Medications. Curr. Top. Med. Chem. 13, 2306–2327.

PT

Aviles-olmos, I., Dickson, J., Kefalopoulou, Z., Djamshidian, A., Kahan, J., 2014. Motor and Cognitive Advantages Persist 12 Months After Exenatide Exposure in Parkinson ’ s Disease. J. Park. Dis. 4, 337–344. doi:10.3233/JPD-140364

RI

Baglietto-vargas, D., Shi, J., Yaeger, D.M., Ager, R., Laferla, F.M., 2016. Neuroscience and Biobehavioral Reviews Diabetes and Alzheimer ’ s disease crosstalk. Neurosci. Biobehav. Rev. 64, 272–287. doi:10.1016/j.neubiorev.2016.03.005

SC

Bamberger, M.E., Harris, M.E., McDonald, D.R., Husemann, J., Landreth, G.E., 2003. A cell surface receptor complex for fibrillar β-amyloid mediates microglial activation. J. Neurosci. 23, 2665–2674.

NU

Barage, S.H., Sonawane, K.D., 2015. Amyloid cascade hypothesis: Pathogenesis and therapeutic strategies in Alzheimer’s disease. Neuropeptides 52, 1–18. doi:10.1016/j.npep.2015.06.008

MA

Bartus, R.T., Dean, R.L., Beer, B., Lippa, a S., 1982. The cholinergic hypothesis of geriatric memory dysfunction. Science 217, 408–414. doi:10.1126/science.7046051

ED

Benilova, I., Karran, E., De Strooper, B., 2012. The toxic Aβ oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat. Neurosci. 15, 349–57. doi:10.1038/nn.3028

EP T

Bhattacharjee, P., Bhattacharyya, D., 2013. Factor v activator from daboia russelli russelli venom destabilizes ββ-amyloid aggregate, the hallmark of alzheimer disease. J. Biol. Chem. 288, 30559–30570. doi:10.1074/jbc.M113.511410 Binder, L.I., Frankfurter, A., Rebhun, L.I., 1985. The distribution of tau in the mammalian central nervous system. J. Cell Biol. 101, 1371 LP-1378.

AC C

Blázquez, E., Velázquez, E., Hurtado-carneiro, V., 2014. Insulin in the brain : its pathophysiological implications for states related with central insulin resistance , type 2 diabetes and alzheimer ’ s disease. Front. Endocrinol. (Lausanne). 5, 1–21. doi:10.3389/fendo.2014.00161 Blennow, K., Dubois, B., Fagan, A.M., Lewczuk, P., de Leon, M.J., Hampel, H., 2015. Clinical utility of cerebrospinal fluid biomarkers in the diagnosis of early Alzheimer’s disease. Alzheimers. Dement. 11, 58–69. doi:10.1016/j.jalz.2014.02.004 Bomfim, T.R., Forny-germano, L., Sathler, L.B., Brito-moreira, J., Houzel, J., Decker, H., Silverman, M.A., Kazi, H., Melo, H.M., Mcclean, P.L., Holscher, C., Arnold, S.E., Talbot, K., Klein, W.L., Munoz, D.P., Ferreira, S.T., Felice, F.G. De, 2012. An anti -diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer ’ s disease – associated A β oligomers. J. Clin. Invest. 122, 1339–1353. doi:10.1172/JCI57256DS1 Braak, H., Braak, E., 1995. Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol. Aging 16, 271–278. Braak, H., Braak, E., Strothjohann, M., 1994. Abnormally phosphorylated tau protein related to

ACCEPTED MANUSCRIPT the formation of neurofibrillary tangles and neuropil threads in the cerebral cortex of sheep and goat. Neurosci. Lett. 171, 1–4. Busche, M.A., Chen, X., Henning, H.A., Reichwald, J., Staufenbiel, M., Sakmann, B., Konnerth, A., 2012. Critical role of soluble amyloid-β for early hippocampal hyperactivity in a mouse model of Alzheimer’s disease. Proc. Natl. Acad. Sci. 109, 8740–8745. Cacace, R., Sleegers, K., Van Broeckhoven, C., 2016. Molecular genetics of early-onset Alzheimer’s disease revisited. Alzheimer’s Dement. 12, 733–748.

PT

Cantwell, M., Salazar, K.E.N., Mint, J.I.M.D.E., Carolina, S., 2007. Therapeutiuc Strategies for the Treatment of Tauopathies: Hopes and Challenges. Alzheimers Dement. 12, 1051– 1065. doi:10.1016/j.jalz.2016.06.006.Therapeutic

RI

Carsi, J.M., Potter, L.T., 2000. m1-Toxin isotoxins from the green mamba (Dendroaspis angusticeps) that selectively block m1 muscarinic receptors. Toxicon 38, 187–198. doi:10.1016/S0041-0101(99)00141-5

SC

Castellano, J.M., Kim, J., Stewart, F.R., Jiang, H., DeMattos, R.B., Patterson, B.W., Fagan, A.M., Morris, J.C., Mawuenyega, K.G., Cruchaga, C., 2011. Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci. Transl. Med. 3, 89ra57-89ra57.

NU

Chen, C., Liao, S., Kuo, J., 2000. Gliotoxic action of glutamate on cultured astrocytes. J. Neurochem. 75, 1557–1565.

MA

Chen, X., Yuan, L.-L., Zhao, C., Birnbaum, S.G., Frick, A., Jung, W.E., Schwarz, T.L., Sweatt, J.D., Johnston, D., 2006. Deletion of Kv4.2 Gene Eliminates Dendritic A-Type K+ Current and Enhances Induction of Long-Term Potentiation in Hippocampal CA1 Pyramidal Neurons. J. Neurosci. 26, 12143–12151. doi:10.1523/JNEUROSCI.2667-06.2006

ED

Chen, Y., Zhang, J., Zhang, B., Gong, C., 2016. Targeting Insulin Signaling for the Treatment of Alzheimer â€TM s Disease. Curr. Top. Med. Chem. 16, 485–492.

EP T

Corder, E.H., Saunders, A.M., Strittmatter, W.J., Schmechel, D.E., Gaskell, P.C., Small, Gw. al, Roses, A.D., Haines, J.L., Pericak-Vance, M. Al, 1993. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science (80-. ). 261, 921– 923.

AC C

Craft, S., Baker, L.D., Montine, T.J., Minoshima, S., Watson, G.S., Claxton, A., Arbuckle, M., Callaghan, M., Tsai, E., Plymate, S.R., Green, P.S., Leverez, J., Cros, D., Gerton, B., 2017. Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment. Arch Neurol. 69, 32–38. doi:10.1001/archneurol.2011.233 Danho, W., Swistok, J., Khan, W., Chu, X.-J., Cheung, A., Fry, D., Sun, H., Kurylko, G., Rumennik, L., Cefalu, J., Cefalu, G., Nunn, P., 2009. Opportunities and Challenges of Developing Peptide Drugs in the Pharmaceutical Industry BT - Peptides for Youth: The Proceedings of the 20th American Peptide Symposium, in: Valle, S. Del, Escher, E., Lubell, W.D. (Eds.), . Springer New York, New York, NY, pp. 467–469. doi:10.1007/978-0-387-73657-0_201 Davidson, M.B., Bate, G., Kirkpatrick, P., 2005. Exenatide. Nat. Rev. Drug Discov. 4, 713–714. doi:10.1038/nrd1828 Dodd, P.R., Scott, H.L., WESTPHALEN, R.I., 1994. EXCITOTOXIC MECHANISMS IN THE PATHOGENESIS OF DEMENTIA. Neurochem. Int 25, 203–219. Donohue, M.C., Sperling, R.A., Petersen, R., Sun, C.-K., Weiner, M.W., Aisen, P.S., 2017. Association Between Elevated Brain Amyloid and Subsequent Cognitive Decline Among

ACCEPTED MANUSCRIPT Cognitively Normal Persons. Jama 317, 2305. doi:10.1001/jama.2017.6669 Drubin, D., Kobayashi, S., Kellogg, D., Kirschner, M., 1988. Regulation of microtubule protein levels during cellular morphogenesis in nerve growth factor-treated PC12 cells. J. Cell Biol. 106, 1583–1591. Drucker, D.J., Nauck, M.A., 2006. The incretin system : glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 368, 1696–705. Duarte, A.I., Moreira, P.I., Oliveira, C.R., 2012. Insulin in Central Nervous System : More than Just a Peripheral Hormone. J. agind Res. 2012. doi:10.1155/2012/384017

PT

Ducancel, F., Rowan, I.E.G., Cassar, I.E., Harvey, A.L., 1991. AMINO ACID SEQUENCE OF A MUSCARINIC TOXIN DEDUCED FROM THE cDNA NUCLEOTIDE SEQUENCE 29, 0–4.

SC

RI

Ebneth, A., Godemann, R., Stamer, K., Illenberger, S., Trinczek, B., Mandelkow, E. -M., Mandelkow, E., 1998. Overexpression of tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: implications for Alzheimer’s disease. J. Cell Biol. 143, 777–794.

NU

Esler, W.P., Wolfe, M.S., 2001. A portrait of Alzheimer secretases--new features and familiar faces. Science (80-. ). 293, 1449–1454.

MA

Esparza, T.J., Zhao, H., Cirrito, J.R., Cairns, N.J., Bateman, R.J., Holtzman, D.M., Brody, D.L., 2013. Amyloid‐beta oligomerization in Alzheimer dementia versus high‐pathology controls. Ann. Neurol. 73, 104–119. Estrada, G., Villegas, E., Corzo, G., 2007. Spider venoms: a rich source of acylpolyamines and peptides as new leads for CNS drugs. Nat. Prod. Rep. 24, 145–161. doi:10.1039/b603083c

ED

Ferreira, I.L., Bajouco, L.M., Mota, S.I., Auberson, Y.P., Oliveira, C.R., Rego, A.C., 2012. Amyloid beta peptide 1–42 disturbs intracellular calcium homeostasis through activation of GluN2B-containing N-methyl-d-aspartate receptors in cortical cultures. Cell Calcium 51, 95–106.

EP T

Fricker, M., Vilalta, A., Tolkovsky, A.M., Brown, G.C., 2013. Caspase inhibitors protect neurons by enabling selective necroptosis of inflamed microglia. J. Biol. Chem. 288, 9145–9152.

AC C

Goedert, M., Spillantini, M.G., 2006. A century of Alzheimer’s disease. Science (80-. ). 314, 777–781. Gomes, G.M., Dalmolin, G.D., Cordeiro, N., Gomez, M. V, Ferreira, J., Rubin, M.A., 2013. The selective A-type K þ current blocker Tx3-1 isolated from the Phoneutria nigriventer venom enhances memory of naïve and A b 25-35 -treated mice. Toxicon 76, 23–27. Griciuc, A., Serrano-Pozo, A., Parrado, A.R., Lesinski, A.N., Asselin, C.N., Mullin, K., Hooli, B., Choi, S.H., Hyman, B.T., Tanzi, R.E., 2013. Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 78, 631–643. Gu, Z., Zhong, P., Yan, Z., 2003. Activation of muscarinic receptors inhibits β-amyloid peptideinduced signaling in cortical slices. J. Biol. Chem. 278, 17546–17556. doi:10.1074/jbc.M209892200 Gudala, K., Bansal, D., Schifano, F., Bhansali, A., 2013. Diabetes mellitus and risk of dementia : A meta-analysis of prospective observational studies. J. Diabetes Investig. 4, 642–650. doi:10.1111/jdi.12087 Gunn, A.P., Wong, X.B.X., Johanssen, X.T., Griffith, X.J.C., Masters, C.L., Bush, A.I., Barnham,

ACCEPTED MANUSCRIPT K.J., Duce, J.A., Cherny, R.A., 2016. Amyloid- Peptide A-3pE-42 Induces Lipid Peroxidation, Membrane Permeabilization, and Calcium Influx in Neurons. J. Biol. Chem. 291, 6134– 6145. doi:10.1074/jbc.M115.655183 Haass, C., Selkoe, D.J., 2007. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid β-peptide. Nat. Rev. Mol. cell Biol. 8, 101–112. Halle, A., Hornung, V., Petzold, G.C., Stewart, C.R., Monks, B.G., Reinheckel, T., Fitzgerald, K.A., Latz, E., Moore, K.J., Golenbock, D.T., 2008. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nat. Immunol. 9, 857–865.

PT

Hardy, J.A., Higgins, G.A., 1992. Alzheimer’s disease: the amyloid cascade hypothesis. Science (80-. ). 256, 184.

RI

Hardy, J., Selkoe, D.J., 2002. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science (80-. ). 297. doi:10.1126/science.1072994

SC

Harel, M., Kleywegt, G.J., Ravelli, R.B., Silman, I., Sussman, J.L., 1995. Crystal structure of an acetylcholinesterase-fasciculin complex: interaction of a three-fingered toxin from snake venom with its target. Structure 3, 1355–1366. doi:10.1016/S0969-2126(01)00273-8

NU

Haring, R., Fisher, A., Marciano, D., Pittel, Z., Kloog, Y., Zuckerman, A., Eshhar, N., Heldman, E., 1998. Mitogen‐Activated Protein Kinase‐Dependent and Protein Kinase C‐Dependent Pathways Link the m1 Muscarinic Receptor to β‐Amyloid Precursor Protein Secretion. J. Neurochem. 71, 2094–2103.

MA

Harvey, A.L., Karlsson, E., 1984. Polypeptide neurotoxin$ from mamba venoms. Harvey, A.L., Robertson, B., 2004. Dendrotoxins : Structure-Activity Relationships and Effects on Potassium Ion Channels 3065–3072.

ED

Heneka, M.T., Carson, M.J., El Khoury, J., Landreth, G.E., Brosseron, F., Feinstein, D.L., Jacobs, A.H., Wyss-Coray, T., Vitorica, J., Ransohoff, R.M., 2015. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 14, 388–405.

EP T

Holscher, C., 2010. Incretin Analogues that have been Developed to Treat Type 2 Diabetes Hold Promise as a Novel Treatment Strategy for Alzheimer â€TM s Disease. Recent Pat. CNS Drug Discov. 5, 109–117.

AC C

Hsieh, C.L., Koike, M., Spusta, S., Niemi, E., Yenari, M., Nakamura, M.C., Seaman, W.E., 2009. A Role for TREM2 Ligands in the Phagocytosis of Apoptotic Neuronal Cells by Microglia. J. Neurochem. 109, 1144–1156. doi:10.1111/j.1471-4159.2009.06042.x Hyman, B.T., Phelps, C.H., Beach, T.G., Bigio, E.H., Cairns, N.J., Carrillo, M.C., Dickson, D.W., Duyckaerts, C., Frosch, M.P., Masliah, E., 2012. National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimer’s Dement. 8, 1–13. Jerusalinsky, D., Cerveñansky, C., Walz, R., Bianchin, M., Izquierdo, I., 1993. A peptide muscarinic toxin from the Green Mamba venom shows agonist-like action in an inhibitory avoidance learning task. Eur. J. Pharmacol. 240, 103–105. doi:10.1016/00142999(93)90554-U Kamat, P.K., Kalani, A., Rai, S., Swarnkar, S., Tota, S., Nath, C., Tyagi, N., 2016. Mechanism of oxidative stress and synapse dysfunction in the pathogenesis of Alzheimer’s disease: understanding the therapeutics strategies. Mol. Neurobiol. 53, 648–661. Klafki, H.-W., Staufenbiel, M., Kornhuber, J., Wiltfang, J., 2006. Therapeutic approaches to

ACCEPTED MANUSCRIPT Alzheimer’s disease. Brain 129, 2840–55. doi:10.1093/brain/awl280 Kober, D.L., Alexander-brett, J.M., Karch, C.M., Cruchaga, C., Colonna, M., Holtzman, M.J., Brett, T.J., 2016. Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms. Elife 5, 1–24. doi:10.7554/eLife.20391 LaFerla, F.M., 2002. Calcium dyshomeostasis and intracellular signalling in alzheimer’s disease. Nat Rev Neurosci 3, 862–872.

PT

Lahmy, V., Meunier, J., Malmström, S., Naert, G., Givalois, L., Kim, S.H., Villard, V., Vamvakides, A., Maurice, T., 2013. Blockade of Tau Hyperphosphorylation and Aβ1–42 Generation by the Aminotetrahydrofuran Derivative ANAVEX2-73, a Mixed Muscarinic and σ1 Receptor Agonist, in a Nontransgenic Mouse Model of Alzheimer’s Disease. Neuropsychopharmacology 38, 1706–1723. doi:10.1038/npp.2013.70

SC

RI

Lei, M., Xu, H., Li, Z., Wang, Z., O’Malley, T.T., Zhang, D., Walsh, D.M., Xu, P., Selkoe, D.J., Li, S., 2016. Soluble A?? oligomers impair hippocampal LTP by disrupting glutamatergic/GABAergic balance. Neurobiol. Dis. 85, 111–121. doi:10.1016/j.nbd.2015.10.019

NU

Levin, S.G., Shamsutdinova, A.A., Godukhin, O. V, 2010. Apamin , a selective blocker of SK Ca channels , inhibits posthypoxic hyperexcitability but does not affect rapid hypoxic preconditioning in hippocampal CA1 pyramidal neurons in vitro. Neurosci. Lett. 484, 35– 38. doi:10.1016/j.neulet.2010.08.012

MA

Lien, S., Lowman, H.B., 2003. Therapeutic peptides. Trends Biotechnol. 21, 556–562. doi:10.1016/j.tibtech.2003.10.005

ED

Lin, L., Georgievska, B., Mattsson, a, Isacson, O., 1999. Cognitive changes and modified processing of amyloid precursor protein in the cortical and hippocampal system after cholinergic synapse loss and muscarinic receptor activation. Proc. Natl. Acad. Sci. U. S. A. 96, 12108–13. doi:10.1073/pnas.96.21.12108

EP T

Liu, Q., Kawai, H., Berg, D.K., 2001. β-Amyloid peptide blocks the response of α7-containing nicotinic receptors on hippocampal neurons. Proc. Natl. Acad. Sci. 98, 4734–4739.

AC C

Liu, Y., Walter, S., Stagi, M., Cherny, D., Letiembre, M., Schulz-Schaeffer, W., Heine, H., Penke, B., Neumann, H., Fassbender, K., 2005. LPS receptor (CD14): a receptor for phagocytosis of Alzheimer’s amyloid peptide. Brain 128, 1778–1789. Maatuk, N., Samson, A.O., 2013. Modeling the binding mechanism of Alzheimer’s A??1-42 to nicotinic acetylcholine receptors based on similarity with snake ??-neurotoxins. Neurotoxicology 34, 236–242. doi:10.1016/j.neuro.2012.09.007 Marcello, E., Epis, R., Saraceno, C., Gardoni, F., Borroni, B., Cattabeni, F., Padovani, A., Di Luca, M., 2012. SAP97-mediated local trafficking is altered in Alzheimer disease patients’ hippocampus. Neurobiol. Aging 33, 422-e1. Marks, J.L., Porte, D., Stafflj, W.L., Basking, D.G., 1990. Localization of insulin receptor mRNA in rat brain by in situ hybridization. Endocrinology 127, 3234–3236. Medeiros, R., LaFerla, F.M., 2013. Astrocytes: conductors of the Alzheimer disease neuroinflammatory symphony. Exp. Neurol. 239, 133–138. Megill, A., Tran, T., Eldred, K., Lee, N.J., Wong, P.C., Hoe, H.-S., Kirkwood, A., Lee, H.-K., 2015. Defective age-dependent metaplasticity in a mouse model of Alzheimer’s disease. J. Neurosci. 35, 11346–11357.

ACCEPTED MANUSCRIPT Mehta, A., Prabhakar, M., Kumar, P., Deshmukh, R., Sharma, P.L., 2013. Excitotoxicity : Bridge to various triggers in neurodegenerative disorders. Eur. J. Pharmacol. 698, 6–18. doi:10.1016/j.ejphar.2012.10.032 Messier, C., Mourre, C., Bontempi, B., Sif, J., Lazdunski, M., Destrade, C., 1991. Effect of apamin, a toxin that inhibits Caa+-dependent K + channels, on learning and memory processes. Brain Res. 551, 322–326.

PT

Minkeviciene, R., Rheims, S., Dobszay, M.B., Zilberter, M., Hartikainen, J., Fulop, L., Penke, B., Zilberter, Y., Harkany, T., Pitkanen, A., Tanila, H., 2009. Amyloid -Induced Neuronal Hyperexcitability Triggers Progressive Epilepsy. J. Neurosci. 29, 3453–3462. doi:10.1523/JNEUROSCI.5215-08.2009

RI

Mishra, P., Ayyannan, S.R., Panda, G., 2015. Perspectives on Inhibiting β‐Amyloid Aggregation through Structure‐Based Drug Design. ChemMedChem 10, 1467–1474.

SC

Mondragón-Rodríguez, S., Trillaud-Doppia, E., Dudilot, A., Bourgeois, C., Lauzon, M., Leclerc, N., Boehm, J., 2012. Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation. J. Biol. Chem. 287, 32040–32053.

MA

NU

Monge-Fuentes, V., Gomes, F.M.M., Campos, G.A.A., de Castro Silva, J., Biolchi, A.M., dos Anjos, L.C., Gonçalves, J.C., Lopes, K.S., Mortari, M.R., 2015. Neuroactive compounds obtained from arthropod venoms as new therapeutic platforms for the treatment of neurological disorders. J. Venom. Anim. Toxins Incl. Trop. Dis. 21, 31. Monte, S.M. de la, Wands, J.R., 2008. Alzheimer ’ s Disease Is Type 3 Diabetes — Evidence Reviewed. J. Diabetes Sci. Technol. 2, 1101–1113.

ED

Mourre, C., Cervera, P., Lazdunski, M., 1987. Autoradiographic analysis in rat brain of the postnatal ontogeny of voltage-dependent Na + channels , Ca2 + -dependent K + channels and slow C a 2 + channels identified as receptors for tetrodotoxin , apamin and ( - ) desmethoxyverapamil. Brain Res. 417, 21–32.

EP T

Mourre, C., Hugues, M., Lazdunski, M., 1986. Quantitative Autoradiographic Mapping in Rat Brain of the Receptor of Apamin, a Polypeptide Toxin Specific for One Class of Ca2÷Dependent K ÷ Channels. Brain Res. 382, 239–249.

AC C

Müller, U.C., Deller, T., Korte, M., 2017. Not just amyloid: physiologi cal functions of the amyloid precursor protein family. Nat. Publ. Gr. doi:10.1038/nrn.2017.29 Nussbaum, R.L., Ellis, C.E., 2003. Alzheimer’s disease and Parkinson’s disease. N. Engl. J. Med. 348, 1356–1364. Olney, J.W., Sharpe, L.G., 1969. Brain lesions in an infant rhesus monkey treated with monosodium glutamate. Science (80-. ). 166, 386–388. Ott, A., Stolk, R.P., Harskamp, F. Van, 1999. Diabetes mellitus and the risk of dementia. Neurology 53, 1937–1997. doi:10.1212/WNL.53.9.1937 Ott, A., Stolk, R.P., Hofman, A., Harskamp, F. Van, Grobbee, D.E., Breteler, M.M.B., 1996. Association of diabetes mellitus and dementia : The Rotterdam Study. Diabetologia 39, 1392–1397. Parsons, C.G., Danysz, W., Dekundy, A., Pulte, I., 2013. Memantine and cholinesterase inhibitors: complementary mechanisms in the treatment of Alzheimer’s disease. Neurotox. Res. 24, 358–369.

ACCEPTED MANUSCRIPT Perry, E., Walker, M., Grace, J., Perry, R., 1999. Acetylcholine in mind: A neurotransmitter correlate of consciousness? Trends Neurosci. 22, 273–280. doi:10.1016/S01662236(98)01361-7 Petersen, R.C., 2011. Mild Cognitive Impairment. N. Engl. J. Med. 364, 2227–2234. doi:10.1056/NEJMcp0910237 Petersen, R.C., Roberts, R.O., Knopman, D.S., Boeve, B.F., Geda, Y.E., Ivnik, R.J., Smith, G.E., Jack, C.R., 2009. Mild cognitive impairment: ten years later. Arch. Neurol. 66, 1447–1455.

PT

Pike, C.J., Burdick, D., Walencewicz, A.J., Glabe, C.G., Cotman, C.W., 1993. Neurodegeneration Induced By Beta-Amyloid Peptides Invitro - the Role of Peptide Assembly State. J. Neurosci. 13, 1676–1687.

RI

Plant, L.D., Webster, N.J., Boyle, J.P., Ramsden, M., Freir, D.B., Peers, C., Pearson, H.A., 2006. Amyloid b peptide as a physiological modulator of neuronal “A”-type K+ current. Neurobiol. Aging 27, 1673–1683. doi:10.1016/j.neurobiolaging.2005.09.038

NU

SC

Prince, M., Wimo, A., Guerchet, M., Gemma-Claire, A., Wu, Y.-T., Prina, M., 2015. World Alzheimer Report 2015: The Global Impact of Dementia - An analysis of prevalence, incidence, cost and trends. Alzheimer’s Dis. Int. 84. doi:10.1111/j.09637214.2004.00293.x

MA

Profenno, L.A., Porsteinsson, A.P., Faraone, S. V, 2010. Meta-Analysis of Alzheimer ’ s Disease Risk with Obesity , Diabetes , and Related Disorders. Biol Psychiatry 67, 505–512. doi:10.1016/j.biopsych.2009.02.013 Prorok, M., Castellino, F.J., 2007. The Molecular Basis of Conantokin Antagonism of NMDA Receptor Function. Curr. Drug Targets 8, 633–642.

ED

Qiu, T., Liu, Q., Chen, Y.X., Zhao, Y.F., Li, Y.M., 2015. A??42 and A??40: similarities and differences. J. Pept. Sci. 21, 522–529. doi:10.1002/psc.2789

EP T

Ragnarsson, L., Mortensen, M., Dodd, P.R., Lewis, R.J., 2002. Spermine modulation of the glutamate NMDA receptor is differentially responsive to conantokins in normal and Alzheimer ’ s disease human cerebral cortex. J. Neurochem. 81, 765–779. Ramírez, V.T., Ramos-Fernández, E., Inestrosa, N.C., 2015. The Activator Mastoparan-7 Promotes Dendritic Spine Formation in Hippocampal Neurons. Neural Plast. 2016.

AC C

Raufman, J., Singh, L., Singh, G., Eng, J., 1992. Truncated Glucagon-like Peptide- 1 Interacts with Exendin Receptors on Dispersed Acini from Guinea Pig Pancreas. J. Biol. Chem. 267, 21432–21437. Reisberg, B., Doody, R., Stöffler, A., Schmitt, F., Ferris, S., Möbius, H.J., 2003. Memantine in moderate-to-severe Alzheimer’s disease. N. Engl. J. Med. 348, 1333–1341. Ren, S., Chen, P., Jiang, H., Mi, Z., Xu, F., Hu, B., Zhang, J., Zhu, Z., 2014. Persistent sodium currents contribute to Aβ1-42-induced hyperexcitation of hippocampal CA1 pyramidal neurons. Neurosci. Lett. 580, 62–67. doi:http://dx.doi.org/10.1016/j.neulet.2014.07.050 Rodríguez-Ithurralde, D., Silveira, R., Barbeito, L., Dajas, F., 1983. Fasciculin, a powerful anticholinesterase polypeptide from Dendroaspis angusticeps venom. Neurochem. Int. 5, 267–274. doi:10.1016/0197-0186(83)90028-1 ROMERO-CURIEL, A., LOPEZ-CARPINTEYRO, D., GAMBOA, C., CRUZ, F.D. LA, ZAMUDIO, S., FLORES, G., 2011. Apamin Induces Plastic Changes in Hippocampal Neurons in Senile Sprague – Dawley Rats. synapse 65, 1062–1072. doi:10.1002/syn.20938

ACCEPTED MANUSCRIPT Samson, A., Scherf, T., Eisenstein, M., Chill, J., Anglister, J., 2002. The mechanism for acetylcholine receptor inhibition by alpha-neurotoxins and species-specific resistance to alpha-bungarotoxin revealed by NMR. Neuron 35, 319–332. doi:10.1016/S08966273(02)00773-0 Selkoe, D.J., 2003. Folding proteins in fatal ways. Nature 426, 900–904. Selkoe, D.J., Hardy, J., 2016a. The amyloid hypothesis of Alzheimer9s disease at 25 years. EMBO Mol. Med. 8, 595–608.

PT

Selkoe, D.J., Hardy, J., 2016b. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol. Med. 8, 1–14. doi:10.15252/emmm.201606210

SC

RI

Silva, J., Monge-Fuentes, V., Gomes, F., Lopes, K., dos Anjos, L., Campos, G., Arenas, C., Biolchi, A., Gonçalves, J., Galante, P., Campos, L., Mortari, M., 2015. Pharmacological alternatives for the treatment of neurodegenerative disorders: Wasp and bee venoms and their components as new neuroactive tools. Toxins (Basel). 7, 3179–3209. doi:10.3390/toxins7083179

NU

Šimić, G., Babić Leko, M., Wray, S., Harrington, C., Delalle, I., Jovanov-Milošević, N., Bažadona, D., Buée, L., de Silva, R., Giovanni, G. Di, Wischik, C., Hof, P.R., 2016. Tau protein hyperphosphorylation and aggregation in alzheimer’s disease and other tauopathies, and possible neuroprotective strategies. Biomolecules 6, 2–28. doi:10.3390/biom6010006

MA

Simons, M., De Strooper, B., Multhaup, G., Tienari, P.J., Dotti, C.G., Beyreuther, K., 1996. Amyloidogenic processing of the human amyloid precursor protein in primary cultures of rat hippocampal neurons. J. Neurosci. 16, 899–908.

EP T

ED

Sperling, R.A., Aisen, P.S., Beckett, L.A., Bennett, D.A., Craft, S., Fagan, A.M., Iwatsubo, T., Jack, C.R., Kaye, J., Montine, T.J., Park, D.C., Reiman, E.M., Rowe, C.C., Siemers, E., Stern, Y., Yaffe, K., Carrillo, M.C., Thies, B., Morrison-Bogorad, M., Wagster, M. V, Phelps, C.H., 2011. Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging and the Alzheimer’s Association workgroup. Alzheimer’s Dement. 7, 1–13. doi:10.1016/j.jalz.2011.03.005 Staay, F.J. Van Der, Fanelli, R.J., Blokland, A., Schmidt, B.H., 1999. Behavioral effects of apamin , a selective inhibitor of the SK Ca -channel , in mice and rats 4.

AC C

Steen, E., Terry, B.M., Rivera, E.J., Cannon, J.L., Neely, T.R., Tavares, R., Xu, X.J., Wands, J.R. , Monte, S.M. De, 2005. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer ’ s disease – is this type 3 diabetes ? J. Alzheimer’s Dis. 7, 63–80. Stewart, C.R., Stuart, L.M., Wilkinson, K., Van Gils, J.M., Deng, J., Halle, A., Rayner, K.J., Boyer, L., Zhong, R., Frazier, W.A., 2010. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat. Immunol. 11, 155–161. Talbot, K., Wang, H., Kazi, H., Han, L., Bakshi, K.P., Stucky, A., Fuino, R.L., Kawaguchi, K.R., Samoyedny, A.J., Wilson, R.S., Arvanitakis, Z., Schneider, J.A., Wolf, B.A., Bennett, D.A., Trojanowski, J.Q., Arnold, S.E., 2012. Demonstrated brain insulin resistance in Alzheimer ’ s disease patients is associated with IGF-1 resistance , IRS-1 dysregulation , and cognitive decline. J. Clin. Invest. 122, 1316–1338. doi:10.1172/JCI59903DS1 Terry, A. V, Buccafusco, J.J., 2003. The cholinergic hypothesis of age and Alzheimer’s diseaserelated cognitive deficits: recent challenges and their implications for novel drug development. J. Pharmacol. Exp. Ther. 306, 821–827.

ACCEPTED MANUSCRIPT Tofoleanu, F., Buchete, N.-V., 2012. Molecular interactions of Alzheimer’s Aβ protofilaments with lipid membranes. J. Mol. Biol. 421, 572–586. Tramutola, A., Arena, A., Cini, C., Butterfield, D.A., 2016. Modulation of GLP-1 signaling as a novel therapeutic approach in the treatment of Alzheimer ’ s disease pathology. Expert Rev. Neurother. 0. doi:10.1080/14737175.2017.1246183 Tsai, I.H., Lu, P.J., Su, J.C., 1996. Two types of Russell’s viper revealed by variation in phospholipases A2 from venom of the subspecies. Toxicon 34, 99–109. doi:10.1016/0041-0101(95)00114-X

PT

Tsetlin, V.I., 2014. Three-finger snake neurotoxins and Ly6 proteins targeting nicotinic acetylcholine receptors : pharmacological tools and endogenous modulators. Trends Pharmacol. Sci. 1–15. doi:10.1016/j.tips.2014.11.003

SC

RI

Tuligenga, R.H., Dugravot, A., Tabák, A.G., Elbaz, A., Brunner, E.J., Kivimäki, M., Singh-manoux, A., 2014. Midlife type 2 diabetes and poor glycaemic control as risk factors for cognitive decline in early old age : a post-hoc analysis of the Whitehall II cohort study. Lancet Diabetes Endocrinol. 2, 228–235. doi:10.1016/S2213-8587(13)70192-X

NU

Vom Berg, J., Prokop, S., Miller, K.R., Obst, J., Kälin, R.E., Lopategui-Cabezas, I., Wegner, A., Mair, F., Schipke, C.G., Peters, O., 2012. Inhibition of IL-12/IL-23 signaling reduces Alzheimer’s disease-like pathology and cognitive decline. Nat. Med. 18, 1812–1819.

MA

Walsh, D.M., Selkoe, D.J., 2004. Deciphering the molecular basis of memory failure in Alzheimer’s disease. Neuron 44, 181–193.

ED

Wang, Q., Rowan, M.J., Anwyl, R., 2004. β-amyloid-mediated inhibition of NMDA receptordependent long-term potentiation induction involves activation of microglia and stimulation of inducible nitric oxide synthase and superoxide. J. Neurosci. 24, 6049–6056.

EP T

Wang, T., Wang, S.-W., Zhang, Y., Wu, X.-F., Peng, Y., Cao, Z., Ge, B.-Y., Wang, X., Wu, Q., Lin, J.T., Zhang, W.-Q., Li, S., Zhao, J., 2014. Scorpion Venom Heat-Resistant Peptide (SVHRP) Enhances Neurogenesis and Neurite Outgrowth of Immature Neurons in Adult Mice by Up-Regulating Brain-Derived Neurotrophic Factor (BDNF). PLoS One 9, e109977.

AC C

Waqar, M., Batool, S., 2015. In silico analysis of binding of neurotoxic venom ligands with acetylcholinesterase for therapeutic use in treatment of Alzheimer ’ s disease. J. Theor. Biol. 372, 107–117. doi:10.1016/j.jtbi.2015.02.028 Weingarten, M.D., Lockwood, A.H., Hwo, S.Y., Kirschner, M.W., 1975. A protein factor essential for microtubule assembly. Proc. Natl. Acad. Sci. U. S. A. 72, 1858–62. doi:10.1073/pnas.72.5.1858 White, M.F., 2004. Insulin Signaling in Health and Disease. Science (80-. ). 302, 1710–1711. Whitehead, G., Regan, P., Whitcomb, D.J., Cho, K., 2017. Ca 2 þ -permeable AMPA receptor : A new perspective on amyloid-beta mediated pathophysiology of Alzheimer â€TM s disease. Neuropharmacology 112, 221–227. doi:10.1016/j.neuropharm.2016.08.022 Wischik, C.M., Novak, M., Edwards, P.C., Klug, A., Tichelaar, W., Crowther, R.A., 1988. Structural characterization of the core of the paired helical filament of Alzheimer disease. Proc. Natl. Acad. Sci. 85, 4884–4888. Woodruff‐Pak, D.S., Lander, C., Geerts, H., 2002. Nicotinic cholinergic modulation: galantamine as a prototype. CNS Drug Rev. 8, 405–426. Yarchoan, M., Toledo, J.B., Lee, E.B., Arvanitakis, Z., Kazi, H., Han, L.-Y., Louneva, N., Lee, V.M.-

ACCEPTED MANUSCRIPT Y., Kim, S.F., Trojanowski, J.Q., Arnold, S.E., 2015. Abnormal serine phosphorylation of insulin receptor substrate 1 is associated with tau pathology in Alzheimer’s disease and tauopathies. Acta Neuropathol. 128, 679–689. doi:10.1007/s00401-014-1328-5 Zhang, X., Wang, X., Zhou, T., Wu, X., Peng, Y., Pittaluga, A.M., 2016. Scorpion Venom HeatResistant Peptide Protects Transgenic Caenorhabditis elegans from β -Amyloid Toxicity Isolation of Scorpion Venom. Front. Pharmacol. 7, 1–9. doi:10.3389/fphar.2016.00227 Zhang, Y., Li, P., Feng, J., Wu, M., 2016. Dysfunction of NMDA receptors in Alzheimer ’ s disease. Neurol Sci 1039–1047. doi:10.1007/s10072-016-2546-5

AC C

EP T

ED

MA

NU

SC

RI

PT

Zhao, W., Lacor, P.N., Chen, H., Lambert, M.P., Quon, M.J., Krafft, G.A., Klein, W.L., 2009. Insulin Receptor Dysfunction Impairs Cellular Clearance of Neurotoxic Oligomeric A ␤ *. J. Biol. Chem. 284, 18742–18753. doi:10.1074/jbc.M109.011015

ACCEPTED MANUSCRIPT Table 1: Peptides isolated from animal venom to treatment of Alzheimer's disease evaluated in experimental models.

Species Dendroaspis angusticeps

α-Neurotoxin

Bungarus multicinctus

Dendrotoxin

Dendroaspis

Targets  Reversible inhibition of AChE  Competitive inhibition of ACh binding  

Blocks K+ channels Increases ACh release Reversible inhibition of AChE

Dendroaspis angusticeps

AC C

Exanatide

Arthropod





Daboia russelli russelli



Haloderma suspectum



EP T

RVV-V peptide

ED

MA

Muscarinic toxin

NU

SC



PT

Peptides Fasciculin

RI

Animal Reptiles



Tx3-1

Phoneutria nigriventer



SVHRP

Buthus martensii Karsch





Inhibition the binding of the 3H-QNB muscarinic antagonist Retrograde memory facilitation (MTX2) Cleave and disrupt the preformed Aβ fibrils Prevent JNKmediated IRS phosphorylation Improved memory Enhanced shortand long- term memory in mice model Amiliotes paralisis induced by Aβ-42 in transgenic Caenorhabditis elegans Reduction in Aβ oligomers and

References Harel et al., 1995 Samson et al., 2002 Tsetlin, 2014 Harvey and Karlsson, 1984; Harvey and Robertson, 2004 Waqar and Batool, 2015 Carsi and Potter, 2000; Ducancel et al., 1991 Jerusalinsky et al., 1993

Bhattacharj ee and Bhattachary ya, 2013 Bomfim et al., 2012

Gomes et al., 2013

Zhang et al., 2016

ACCEPTED MANUSCRIPT

Apis millifera



 

Wasp



Conantoxin-G

Conus genus



Staay et al., 1999 Romerocuriel et al., 2011

Ramírez et al., 2015

NU EP T

ED

MA



AC C

Marine Animal

SC

RI

Mastoparan-7

PT

Apamin

superoxide production Enhance memory in MWM and Passive Avoidance Test Incremented the spine density and dendritic length Modulation in the SK channels Increases dendritic spine formation in hippocampal neurons by activation of Gα0 protein Antagonize the NMDA receptor Displacement of spermineenhanced [3H]MK-801 binding

Prorok and Castellino, 2007 Ragnarsson et al., 2002