CELL-TYPE DEPENDENT ALZHEIMER'S DISEASE PHENOTYPES: PROBING THE BIOLOGY OF SELECTIVE NEURONAL VULNERABILITY

P204

Podium Presentations: Sunday, July 16, 2017

functional brain networks characterized by large-scale resting state functional magnetic resonance imaging (rs-fMRI) data in healthy subjects. Regional distribution patterns of increased PET-evidenced tau pathology or decreased GM intensity in AD compared to controls were characterized in two independent samples of prodromal and manifest AD cases (Swedish BioFINDER study, n¼44; ADNI study, n¼35). Results: In the BioFINDER study we found that the tau pattern involved predominantly inferior, medial, and lateral temporal cortical areas, the precuneus, and lateral parietal and occipital cortex (Figure 1). This pattern overlapped primarily with the dorsal attention, and to some extent with higher visual, limbic, and parts of the default-mode network. PET-evidenced tau pathology in the ADNI replication sample, which represented a more prodromal group of AD cases, was less pronounced but showed a highly similar spatial distribution profile, suggesting an earlier-stage snapshot of a consistently progressing regional pattern. Preliminary analyses of atrophy patterns in the BioFINDER sample suggested an overlapping pattern with tau spread but with markedly less isocortical involvement. Conclusions: Our results indicate that the regional deposition of tau aggregates in AD predominantly affects higherorder cognitive over primary sensory-motor networks, but does not appear to be specific for the default-mode or related limbic networks. Less isocortical involvement of GM atrophy may reflect a protracted process of tau-mediated neurodegeneration.

Karen E. Duff1,5,6, 1Columbia University Medical Center, New York, NY, USA; 2SUNY Downstate, Brooklyn, NY, USA; 3Weill Cornell Medical College, New York, NY, USA; 4Columbia University, New York, NY, USA; 5 New York State Psychiatric Institute, New York, NY, USA; 6Taub Institute for Research on Alzheimer’s Disease, New York, NY, USA. Contact e-mail: [email protected] Background: The ε4 allele of apolipoprotein E (APOE) is the domi-

nant genetic risk factor for late-onset Alzheimer’s disease (AD). However, why the APOE4 variant is associated with increased risk of AD remains a source of debate. Methods: We investigated the phenotype of an APOE4 mouse model in the absence of overt AD pathology using three complementary techniques. First, we used a variant of fMRI to map brain metabolism in the hippocampal formation of young and old APOE3 vs. APOE4 mice. Next, we performed in vitro and in vivo electrophysiology on hippicampal slices from aged APOE3 vs. APOE4 mice. Finally, we used metabolite profiling to investigate the levels of energy-related metabolites in the entorhinal cortex (EC). Results: We observed that aged APOE4 mice demonstrate hypermetabolism in the hippocampal formation, most notably in the EC. Further analysis using in vitro and in vivo electrophysiology demonstrated that the EC of aged APOE4 mice, as well as the dentate gyrus and subiculum, were hyperexcitable. In addition, metabolomic analysis in the EC showed that this increased activity in the EC is associated with an increase in the levels of several important small molecules related to energy metabolism, including ATP. Conclusions: These results demonstrate that aged APOE4 mice possess a hypermetabolic phenotype, primarily centered around the EC, similar to that which has been observed in AD mouse models and in human AD. We believe that the association of the APOE4 genotype with hypermetabolism may contribute to the increased risk of AD among APOE4 carriers. O1-07-02

CELL-TYPE DEPENDENT ALZHEIMER’S DISEASE PHENOTYPES: PROBING THE BIOLOGY OF SELECTIVE NEURONAL VULNERABILITY

Christina Muratore, Brigham and Women’s Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Contact e-mail: cmuratore@ partners.org Background: Alzheimer’s disease (AD) is a highly prevalent neuro-

SUNDAY, JULY 16, 2017 ORAL SESSION O1-07 MOLECULAR AND CELL BIOLOGY: MECHANISMS OF CELLULAR INJURY FROM TAU AND BETA-AMYLOID O1-07-01

APOE4 INDUCES ENTORHINAL CORTEX HYPERMETABOLISM IN THE ABSENCE OF OVERT ALZHEIMER’S DISEASE PATHOLOGY

Tal Nuriel1, Usman Khan1, Sergio Angulo2, Archana Ashok1, Steven S. Gross3, S Abid Hussaini1, Herman Moreno2, Scott A. Small4,

degenerative disorder characterized by extracellular plaques composed of amyloid b-protein (Ab) and intraneuronal tangles consisting of altered forms of the Tau protein. AD induces progressive memory impairment and cognitive decline in the virtual absence of motor and sensory deficits during its early and middle course. A major unresolved question is the basis for this selective neuronal vulnerability: why are cells in distinct brain regions differentially susceptible to neurodegeneration in AD? Ab, which plays a central role in AD pathogenesis, is generated throughout the brain, yet some regions outside of the limbic and cerebral cortices such as midbrain, hindbrain and spinal cord are relatively spared from Ab plaque deposition and synapse loss. Methods: Here, we examine neurons derived from induced pluripotent stem cells (iPSCs) of patients harboring an AD-causing APP mutation (APPV717I) to quantify AD-relevant phenotypes following directed differentiation to rostral fates (vulnerable) and caudal fates (relatively spared) in AD. Results: We quantitatively compare control and APPV717I iPSCs and find that caudal neurons differ from rostral neurons in both their generation of and responsiveness toAb species, with rostral neurons being more sensitive to fAD mutation than caudal neurons. APPV717I neurons directed to caudal neuronal fates

Podium Presentations: Sunday, July 16, 2017

generated Ab with a lower 42:40 ratio and higher 38:42 ratio than rostral neurons. Further, we show that APPV717I neurons express higher levels of total and phospho-Tau proteins relative to control neurons when directed to a rostral neuronal fate, but not when directed to a caudal neuronal fate. Finally, we demonstrate that neurons of these different cell fates respond differentially to soluble extracts of clinically and neuropathologically typical ‘sporadic’ AD brains. The AD extracts induce an elevation in the phosphorylation of Tau in forebrain neurons, and this is specifically dependent upon the Ab present in these extracts. However, when exposed to the same AD extracts, Tau phosphorylation is not affected in neurons directed to caudal fates. Conclusions: Taken together, our results suggest that both APP processing and Tau homeostasis are differentially altered between neuronal subtypes that are relatively vulnerable or resistant to AD.

O1-07-03

SYNAPTIC RESILIENCE TO TAU AND AMYLOID BETA OLIGOMERS INDUCED BY NEURAL STEM CELL-DERIVED EXOSOMES

Maria-Adelaide Micci1, Balaji Krishnan1, Wenru Zhang1, Elizabeth Bishop1, Steve Kernie2, Rakez Kayed1, Giulio Taglialatela1, 1 University of Texas Medical Branch, Galveston, TX, USA; 2Columbia University, New York, NY, USA. Contact e-mail: [email protected] Background: Certain individuals remain cognitively intact

despite the presence of Alzheimer’s Disease (AD) neuropathology, suggesting that there is a way for the brain to evade AD-dementia. Understanding the involved mechanism(s) would reveal a novel therapeutic concept for AD based on inducing cognitive resilience. We previously found that these resilient individuals have synapses resistant to the binding of toxic oligomers of both tau and amyloid beta (which have been shown to synergistically converge onto synapses and disrupt their function) along with displaying higher numbers of neural stem cells (NSC) in the hippocampus. Our objective was to investigate a possible link between the two phenomena testing the hypothesis that NSC-derived exosomes render synapse resistant to toxic tau and Abeta oligomers, thus preventing oligomer-driven synaptic dysfunction and memory deficits. Methods: Exosomes from the culture medium of undifferentiated and differentiated (MN) NSC were administered ex vivo and in vivo to test their effect on oligomer synaptic binding, oligomer-induced synaptic dysfunction and memory deficits using wt and tg mice with modifiable levels of NSC. Exosome miRNA’s were analyzed by deep sequencing. Results: NSC exosomes, not MN exosomes, decreased oligomer synaptic binding, prevented oligomer-induced LTP deficit and opposed oligomerdriven memory impairment. Abolishing NSC in vivo increased oligomer synaptic binding (a phenomenon reversed by NSC exosomes but not MN exosomes). Specific miRNA present only in NSC exosomes, possibly mediating such effects, were also identified. Conclusions: These results suggest a novel mechanism involving NSC-derived exosomes reducing synaptic vulnerability to both Tau and Ab oigomers, thus allowing individuals with increased neurogenesis to resist AD cognitive decline. They also illustrate a previously unappreciated target for the development of a new treatment concept for AD centered on inducing brain resilience by delivery of NSC-derived exosome or their cargo miRNAs. Supported by NIA/NIH 5R01AG042890 and the Kleberg Foundation.

O1-07-04

P205

PHENOTYPIC RESCUE IN A MOUSE MODEL OF TAUOPATHY BY EARLY MODULATION OF TAU ISOFORMS’ RELATIVE CONTENT

Sonia Espindola1, Ana Damianich1, Manuela Sartor1, Juan Belforte2, JeanMarc Gallo3, Maria Elena Avale1, 1Instituto de Investigaciones en Ingenierıa genetica y Biologıa Molecular (INGEBI-CONICET), Buenos Aires, Argentina; 2Facultad de Medicina UBA, Buenos Aires, Argentina; 3 Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom. Contact e-mail: elena.avale@conicet. gov.ar Background: Tauopathies including Alzheimer’s disease are characterized by the presence of neuronal aggregates of the protein tau in insoluble paired helical filaments. Tau is a microtubule-associated protein, which participates in microtubule dynamics and axonal transport. Alternative splicing of exon 10 (E10) in the Tau transcript produces protein isoforms with three (3R) or four (4R) microtubule binding repeats, expressed in equal amounts in the normal adult human brain. Several tauopathies are associated with mutations affecting E10 alternative splicing, leading to an imbalance between 3R/4R isoforms concomitant with the neurodegenerative process. Methods: We used a genetic engineering strategy to modulate Tau isoforms in vivo which were tested it in a mouse model of tauopathy (Htau). Htau mice show insoluble Tau accumulation in cortical areas with cognitive deficit from 9 months old and early motor impairment in the rotarod task. The relative content of Tau isoforms was modulated in specific brain nuclei (Prefrontal cortex, striatum or hippocampus) of adult hTau mice, by delivering trans-splicing constructs that induce RNA reprogramming of the endogenous tau transcript using lentiviral vectors (Avale et al 2013, Lacovich er al 2016). Results: Treated mice displayed significant changes in 3R:4R tau relative contents, showed reductions of insoluble Tau in the cortex, and a significant functional recovery, evidenced by biochemical, electrophysiological and behavioural analyses. Conclusions: Our results indicate that early local modulation of Tau isoform balance prevent tauopathy-phenotypes in the htau model, rising new perspectives for future therapeutic interventions.

O1-07-05

REGULATED RELEASE OF HYPERPHOSPHORYLATED, AGGREGATED AND SEEDING COMPETENT TAU FROM RODENT BRAINS AND HUMAN SYNAPTOSOMES

Emanuele Sher1, Francesca Mazzo1, MIchael Hutton2, Michael J. O’Neill2, Suchira Bose2, Caroline Kerridge2, Tracey K. Murray2, Olivera Grubisha2, Daniel Ursu2, Lisa Broad2, Helen Elizabeth Sanger1, Yaming Wang3, Feng Pan4, James Monn4, Jeffrey M. Witkin5, Xia Li5, Giampietro Schiavo6, Michel Goedert7, 1Eli Lilly, Windlesham, United Kingdom; 2Eli Lilly & Co Ltd, Windlesham, United Kingdom; 3Eli Lilly and Company, Indianapolis, IN, USA; 4Eli Lilly and Co, Indianapolis, IN, USA; 5Eli-Lilly and Company, Indianapolis, IN, USA; 6University College London, London, United Kingdom; 7MRC Laboratory of Molecular Biology, Cambridge, United Kingdom. Contact e-mail: [email protected] Background: Tau is a microtubule binding protein expressed in

neuronal axons and nerve terminals. Mutations in tau are known to cause different neurological diseases and tau pathology, in the form of aggregates and tangles, is a hallmark of Alzheimer’s disease. Tau pathology in AD starts in the entorhinal cortex but “spreads” along synaptically connected areas as the disease progresses. Understanding how tau is trafficked to the nerve terminal, secreted, and taken up by postsynaptic neurons could lead to the