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Targeting Synaptic Dysfunction in Alzheimer's Disease

Targeting Synaptic Dysfunction in Alzheimer's Disease

Wednesday, May 18, 2011

The New York Academy of Sciences

Optimal functioning of neural networks is critical to the complex cognitive processes of memory, language, emotion, and reasoning that deteriorate in Alzheimer's disease. Understanding the mechanisms by which synaptic connections are formed and create neural networks is crucial to developing new drugs to protect and maintain neuronal function and connectivity. This conference will provide an overview of the process of synaptic plasticity in normal aging and in neurodegenerative disease, and outline therapeutic strategies to preserve vital neural connections.

Networking reception to follow.

Photo credit: Dr. Barbara Calabrese, University of California San Diego, Halpain Laboratory


*Presentation times are subject to change.

8:30 AM

Registration and Continental Breakfast

9:00 AM

Welcome and Opening Remarks
Sonya Dougal, PhD, The New York Academy of Sciences
Howard M. Fillit, MD, Alzheimer’s Drug Discovery Foundation

SESSION I: Overview of Synaptic Function in Aging and Alzheimer's Disease

9:20 AM

Overview of Synaptic Pathology in Aging and Alzheimer's Disease
Vahram Haroutunian, PhD, Mount Sinai School of Medicine

10:00 AM

Synaptic Dysfunction in Aging and Disease
Mark P. Mattson, PhD, National Institute on Aging

10:40 AM

Coffee Break

SESSION II: Synaptic Targets for Drug Discovery

11:15 AM

Targeting Neuronal Calcium Signaling to Halt AD-linked Synaptic Dysfunction
Grace Stutzmann, PhD, Rosalind Franklin University / The Chicago Medical School

11:45 AM

Targeting CREB through Phosphodiesterase Inhibitors
Ottavio Arancio, PhD, Columbia University

12:15 PM

Neuroprotective Strategies: BDNF and NGF
Barbara L. Hempstead, MD, PhD, Weill Medical College of Cornell University

12:45 PM

Lunch Break

1:45 PM

Dysregulation of Lipid Signaling in Alzheimer's Disease
Gilbert Di Paolo, PhD, Columbia University

2:15 PM

Aß Oligomer Binding to Post-Synaptic Prion Protein Activates Fyn to Mediate Neuronal Dysfunction
Stephen M. Strittmatter, MD, PhD, Yale University School of Medicine

2:45 PM

Targeting Mitochondrial-derived ROS to Reverse Synaptic Plasticity and Memory Impairments in Alzheimer's Disease
Eric Klann, PhD, New York University

3:15 PM

Targeting Gamma-Secretase Activating Protein for Alzheimer’s Disease
Lawrence P. Wennogle, PhD, Intra-Cellular Therapeutics

3:45 PM

Closing Remarks
Howard M. Fillit, MD, Alzheimer's Drug Discovery Foundation

4:00 PM

Networking Reception

5:00 PM



Howard M. Fillit, MD

Alzheimer's Drug Discovery Foundation

Howard Fillit, MD, a geriatrician, neuroscientist and leading expert in Alzheimer's disease, is the founding Executive Director of the Alzheimer's Drug Discovery Foundation. Dr. Fillit has had a distinguished academic medicine career at The Rockefeller University and The Mount Sinai School of Medicine where he is currently a clinical professor of geriatrics, medicine and neuroscience. From 1995-1998, he was the corporate medical director for Medicare at New York Life, providing program leadership for over 125,000 elderly people in several regional US markets. Throughout his career, Dr. Fillit has maintained a limited private practice in Manhattan in consultative geriatric medicine with a focus on Alzheimer's disease. He has also served as a consultant to pharmaceutical and biotechnology companies, health care organizations and philanthropies. He is the author or co-author of more than 300 scientific and clinical publications, and is the senior editor of the leading international Textbook of Geriatric Medicine and Gerontology. Dr. Fillit has received several awards and honors including the Rita Hayworth Award for Lifetime Achievement.

Sonya Dougal, PhD

The New York Academy of Sciences


Ottavio Arancio, MD, PhD

The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University

Dr. Ottavio Arancio received his PhD and MD from the University of Pisa (Italy). From 1981 to 1986 he took residency training in Neurology at the University of Verona (Italy). Dr. Arancio has held Faculty appointments at Columbia University, NYU School of Medicine and at SUNY HSCB. In 2004 he became Faculty member of the Dept of Pathology & Cell biology and The Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University. His honors include the "G. Moruzzi Fellowship" (Georgetown University), the "Anna Villa Rusconi Foundation Prize" (Italy), the "INSERM Poste vert Fellowship" (France), the AHAF centennial Award (2007), the Zenith Award (2007), the Margaret Cahn Research Award (2008), and the Edward N. and Della L. Thome Memorial Foundation Award (2010).

Dr. Arancio is a cellular neurobiologist who has contributed to the characterization of the mechanisms of learning in both normal conditions and during neurodegenerative diseases. During the last ten years he has pioneered the field of mechanisms of synaptic dysfunction in Alzheimer's disease. Dr. Arancio's laboratory has focused primarily on events triggered by amyloid protein. These studies, which have suggested new links between synaptic dysfunction and amyloid protein, are of a general relevance to the field of Alzheimer's disease both for understanding the etiopathogenesis of the disease and for developing therapies aiming to improve the cognitive symptoms.

Dr. Arancio has been recently featured on

Gilbert Di Paolo, PhD

Columbia University

Gilbert Di Paolo received a PhD in biology under the supervision of Dr. Gabriele Grenningloh from the University of Lausanne, Switzerland, in 1998. Following postdoctoral training at Yale University, USA, with Pietro De Camilli he obtained a faculty appointment at Columbia University Medical Center, USA, in 2005. He is currently an Assistant Professor in the Department of Pathology and Cell biology and Taub Institute. His research is focused on the role of phosphoinositides and other phospholipids in the regulation of synaptic function. More recently, his laboratory has uncovered important links between lipid dysregulation and synaptic malfunction in mouse genetic models of Alzheimer's disease and Down syndrome.

Vahram Haroutunian, PhD

Mount Sinai School of Medicine

Dr. Haroutunian joined the faculty at The Mount Sinai School of Medicine in the summer of 1982 after completing postdoctoral training at Princeton University. He Professor of Psychiatry. Dr. Haroutunian came to Mount Sinai after completing a postdoctoral training program at Princeton concentrating on research in development and in aging. His research interests since joining the Mount Sinai faculty have centered on the neurobiology of Alzheimer's disease and schizophrenia. He directs the NIA funded program project grant entitled Clinical and Biological Studies of Early Alzheimer's disease and the Mount Sinai Aging, Dementia and Mental Illness Brain Bank. His research during the past few years has focused on the neurobiology of dementia and successful aging. His most recent research is directed at distinguishing between the neurobiological substrates of cognitive health and compromise in young-old and oldest-old persons as well as the role of modifiable cardiovascular risk factors in dementia prevention.

The primary aims of his mental illness related studies has been to understand the neurobiology of schizophrenia. He and his colleagues described how abnormalities in myelin, the fatty coating around nerves that acts as an insulator and speed of signal transmission enhancer, are characteristic biological features of schizophrenia. This has spurred significant studies by his group and that of others into how information processing is degraded in the brain of persons with schizophrenia.

Barbara L. Hempstead, MD, PhD

Weill Medical College of Cornell University

Dr. Hempstead is a Professor of Medicine at Weill Cornell Medical College, and Co-Chief of the Division of Hematology and Medical Oncology. She obtained her MD and PhD from Washington University Scool of Medicine, and completed postdoctoral and clinical training at Weill Cornell Medical College. Her laboratory focuses on the biological actions of neurotrophins, specifically BDNF and NGF. These growth factors play critical roles in neuronal differentiation and survival, as well as modulating synaptic transmission. Her laboratory first postulated a biological role for the precursor forms of neurotrophins (proneurotrophins), and subsequently has identified distinct roles for proneurotrophins in inducing neuronal death, and impairing synaptic transmission. Her research focuses on using genetic models to delineate the role of neurotrophins in establishing neuronal circuitry, modulating synaptic transmission, and acting as injury-induced cytokines. She is a prior Chair of the Gordon Conference on "Neurotrophic Factors."

Eric Klann, PhD

New York University

Eric Klann is Professor of Neural Science and Biology at New York University. He received his PhD. from the Medical College of Virginia, did postdoctoral training at Baylor College of Medicine with Dr. David Sweatt, and previously held faculty positions at the Univeristy of Pittsburgh and Baylor College of Medicine. His lab uses a multidisciplinary approach, utilizing pharmacological, biochemical, molecular, genetic, electrophysiological, and behavioral techniques. His primary research interests are focused on the role of redox signaling and the mechanisms of translational control during long-lasting hippocampal synaptic plasticity and memory, and how these mechanisms are altered in mouse models of intellectual disability, autism, aging, and Alzheimer's disease. Dr. Klann is an Associate Editor for the Journal of Neuroscience, Molecular Brain, and Neurobiology of Learning and Memory, and serves on the Scientific Advisory Boards of the Foundation for Angelman Syndrome Therapeutics and the Fragile X Outcomes Measures Group of the National Institutes of Health.

Mark P. Mattson, PhD

National Institute on Aging

After receiving his PhD degree from the University of Iowa, Dr. Mattson completed a postdoctoral fellowship in Developmental Neuroscience at Colorado State University. He then joined the Sanders–Brown Center on Aging and the Department of Anatomy and Neurobiology at the University of Kentucky College of Medicine where he advanced to a Full Professor. In 2000, Dr. Mattson took the position of Chief of the Laboratory of Neurosciences at the National Institute on Aging in Baltimore, where he leads a multi-faceted research team that applies cutting-edge technologies in research aimed at understanding molecular and cellular mechanisms of brain aging and the pathogenesis of neurodegenerative disorders. He is also a Professor in the Department of Neuroscience at Johns Hopkins University School of Medicine.

Dr. Mattson is considered a leader in the area of cellular and molecular mechanisms underlying neuronal plasticity and neurodegenerative disorders, and has made major contributions to understanding the pathogenesis of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and stroke, and to their prevention and treatment. Dr. Mattson's published findings are highly regarded: he has an 'h factor' of 130 and has been the most cited neuroscientist in the world during the past 15 years according to the ISI information database. He has received many awards including the Metropolitan Life Foundation Medical Research Award, the Alzheimer's Association Zenith Award, the Jordi Folch Pi Award, the Santiago Grisolia Chair Prize, several Grass Lectureship Awards, and he was elected an AAAS Fellow. He is Editor-in-Chief of NeuroMolecular Medicine and Ageing Research Reviews, and has been/is a Managing or Associate Editor of the Journal of Neuroscience, Trends in Neurosciences, the Journal of Neurochemistry, the Neurobiology of Aging, and the Journal of Neuroscience Research. Dr. Mattson has served on several NIH study sections and on scientific advisory boards for many research foundations. He has trained more than 70 postdoctoral and predoctoral scientists, and has made major contributions to the education of undergraduate, graduate and medical students.

Stephen M. Strittmatter, MD, PhD

Yale University School of Medicine

Stephen M. Strittmatter earned his undergraduate degree from Harvard College, summa cum laude, in 1980. He completed M.D. and Ph.D. training at Johns Hopkins in 1986 with mentorship from Solomon H. Snyder, M.D. He then moved to Massachusetts General Hospital for a medical internship and an Adult Neurology residency. While at Massachusetts General Hospital, he worked as a Research Fellow with Mark Fishman, M.D., exploring the molecular basis of axonal guidance. After a year as Fellow, he served briefly as an Assistant Professor at Harvard Medical School before moving to Yale University in 1993. He is currently holds the Vincent Coates Professorship of Neurology and founded the Yale Program in Cellular Neuroscience, Neurodegeneration and Repair. His research on axonal growth during development and regeneration has been recognized by honors from the Ameritec Foundation, the John Merck Fund, the Donaghue Foundation, the McKnight Foundation, the Jacob Javits Award of the NINDS and the American Academy of Neurology.

Grace E. Stutzmann, PhD

Rosalind Franklin University / The Chicago Medical School

Grace Stutzmann received her PhD from the Center for Neural Science at New York University in 1999, working with Joseph LeDoux. Following this, she was a postdoctoral fellow with George Aghajanian at Yale University Medical School. A second post doctoral research fellow position followed at UC Irvine, working with Ian Parker and Frank LaFerla in the Department of Neurobiology and Behavior and Institute for Brain Aging and Dementia. Currently, she is an Assistant Professor in Neuroscience at Rosalind Franklin University / The Chicago Medical School. Her research focuses on studying early pathogenic mechanisms contributing to AD pathogenesis, and uncovering novel therapeutic strategies to prevent disease progression. Her primary techniques include live cell imaging, electrophysiology, and molecular approaches in mouse models of AD, with particular expertise in 2-photon calcium imaging and patch clamp recordings in brain slice preparations. Grace is a member of the Society for Neuroscience, and the Society of General Physiologists.

Lawrence P. Wennogle, PhD

Intra-Cellular Therapeutics

Dr. Wennogle received his Ph.D. in Biochemistry from the University of Colorado, Boulder working under Drs. Howard Berg and Marvin Caruthers where he studied the structure of red blood cell membranes. He then completed two post-doctoral positions, one at the University of Colorado and the second at the Pasteur Institute in Paris, France, working under Jean-Pierre Changeux on the structure-function of the nicotinic acetylcholine receptor for Torpedo mamorata. For the past 30 years, Dr. Wennogle has been involved in the research and development in the pharmaceutical industry aimed at discovery of novel pharmaceutical entities for human diseases. He was a Staff Scientist and Principal Research Fellow at Ciba-Geigy/Novartis for 19 years, where he led drug discovery programs for CNS disorders, cardiovascular disease, diabetes and inflammation, and served on an “Expert Committee in Molecular Biology” with world-wide responsibility to evaluate new technologies. With his broad expertise in drug discovery and the biochemical basis of disease, Dr. Wennogle supervises Intra-Cellular Therapies (ITI) development of small molecule therapeutics for neurodegenerative and neuropsychiatric disorders. ITI currently has a clinical candidate for schizophrenia undergoing phase 2 clinical trials. Dr. Wennogle is a Fellow of the New York Academy of Sciences and has co-authored over 50 scientific publications. He is a member of the New York Academy of Sciences, the American Association for the Advancement of Science, the American Chemical Society, Schizophrenia International Research and the Society for Neurosciences. He has adjunct appointments at Columbia University in the Department of Pharmacology and at University of Medicine and Dentistry, New Jersey in the Graduate School of Biomedical Sciences. His current focus is the development of novel therapeutics for cognitive dysfunction.


Overview of Synaptic Pathology in Aging and Alzheimer's Disease

Vahram Haroutunian, PhD, The Mount Sinai School of Medicine and JJ Peters VAMC, New York

Effective neurotransmission requires an orchestrated series of interactions between various proteins that encapsulate neurotransmitters and exocytose them into the synaptic cleft. Since effective neurotransmission and neurotransmitter release must underlie normal cognitive function, impairments in the levels or functions of synaptic proteins are likely involved in the cognitive deficits of persons with dementia. Different proteins serve different functions within the synaptic boutons and include proteins associated with the vesicular membrane (e.g., synaptophysin, synaptotagmin); the presynaptic membranes, where they participate in the fusion of synaptic vesicles to the synaptic membrane promoting exocytosis (e.g., SNARE complex constituents SNAP-25, Syntaxin,Septin5, and Synaptobrevin);or reside in the presynaptic cytoplasm or other compartments, where they aid in fusion/secretory processes. The levels and distributions of some synaptic proteins have been investigated in AD and have been consistently shown to be reduced and associated with dementia. However, the relationship of functionally different synaptic proteins with dementia, dementia in young-old and oldest-old persons, and with the multiple neuropathological and biochemical deficits associated with Alzheimer's disease has not been studied extensively. Recent studies in our laboratories have focused on the interrelationships between synaptic proteins, their mRNA expression and different indices of AD neurobiology in both young-old and oldest-old persons. These studies have revealed that althoughother dementia-associated hallmarks of AD neuropathology (NPs and NFTs) become less prominent with increasing age, synaptic marker abnormalities in dementia remain constant with increasing age and may represent a neuropathology-independent substrate of dementia spanning all ages.

Synaptic Dysfunction in Aging and Disease

Mark P. Mattson, PhD, Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore

The organization of neuronal microcircuits that control information flow through all brain regions involved in cognitive processing consists of excitatory glutamatergic projection neurons and inhibitory GABAergic interneurons Activity of glutamatergic neurons is modulated by synaptic inputs from noradrenergic, serotonergic and cholinergic neurons. An excitatory imbalance resulting in cellular Ca2+ dysregulation may occur in normal aging and more so in Alzheimer's disease (AD) as the result of oxidative and metabolic stress. Synaptic dysfunction may result, in part, from amyloid β-peptide (Aβ)-associated redox reactions that simultaneously promote Aβ aggregation and cell membrane-associated oxidative stress. The function and structural integrity of synapses is compromised as the result of oxidative impairment of ion-motive ATPases, and glucose and glutamate transporters, thereby rendering the neurons vulnerable to energy depletion, Ca2+ overload and neurofibrillary degeneration. The good news is that the function of synapses involved in cognition can be preserved by reduction of energy intake and regular exercise which activate signaling pathways that increase the production of proteins that protect neurons against oxidative and metabolic stress (e.g., BDNF, protein chaperones, mitochondrial uncoupling proteins, and redox enzymes). Our recent findings suggest that signaling pathways that mediate health benefits of exercise and energy restriction in the periphery may also protect neurons and promote synaptic plasticity. One such pathway, involving PI3 kinase/Akt and the transcription factor CREB, can be activated by the peptide hormone GLP1, and a long-acting GLP1 analog called Exendin-4/Byetta developed for treatment of diabetes and now being tested in AD patients.

Targeting Neuronal Calcium Signaling to Halt AD-linked Synaptic Dysfunction

Grace E. Stutzmann, PhD, Rosalind Franklin University / The Chicago Medical School

Neuronal calcium signaling is fundamental to a myriad of synaptic processes, including neurotransmission, long term plasticity, and vesicle release. Because of this, neurons dedicate substantial metabolic resources to maintain calcium homeostasis and protect network stability. In neurodegenerative diseases involving calcium disruptions, such as Alzheimer's disease (AD), alterations in calcium homeostasis have direct effects on synaptic transmission and plasticity expression, and by association, long-term memory encoding. In AD, proximal pathogenic alterations involve dysregulated ER calcium release via ryanodine receptor (RyR) and IP3R channels, and we have previously shown increased RyR-evoked calcium responses in dendrites and spines of AD mice at young ages. The downstream implications are wide-ranging, but within synaptic compartments, the RyR-mediated calcium alterations introduce shifts in membrane excitability, synaptic transmission and synaptic plasticity thresholds.

Here we present the functional implications of early calcium signaling abnormalities for synaptic transmission and plasticity in AD mouse models, and offer novel pharmacological approaches to preserve functional synaptic properties in AD mice prior to late disease stages associated with synaptic and memory loss. Using 2-photon calcium imaging, patch clamp electrophysiology, and field potential recordings in hippocampal brain slice preparations from 6-12 week old AD and NonTg mice, we demonstrate sensitized RyR-evoked calcium responses in pre- and post-synaptic compartments of AD hippocampal neurons. Presynaptically, disrupted ER calcium alters neurotransmitter release properties and depletes vesicular stores, while postsynaptically, aberrant RyR-evoked calcium release interacts with calcium-dependent plasma membrane channels to alter membrane excitability. Manipulating RyR function revealed notable differences in synaptic plasticity between NonTg and AD mice as well. Acute RyR antagonism blocked LTP and LTD in NonTg mice, however, this same treatment converted LTP to mild LTD, and markedly enhanced LTD, in 3xTg-AD mice. Notably, chronic treatment with RyR blockers had little effect in NonTg mice, yet, this same treatment normalized calcium signaling in the AD mice back to within control conditions. This includes reversing the aberrant ER calcium responses, altered basal synaptic transmission, and impaired plasticity expression in AD mice back to patterns observed in NonTg mice. Therefore, this RyR-targeted approach to normalizing aberrant calcium signaling early in the disease process offers an optimistic therapeutic approach to preserving synaptic and cognitive function in AD.

Targeting CREB through Phosphodiesterase Inhibitors

Ottavio Arancio, MD, PhD, Columbia University Medical Center

Existing Alzheimer's disease (AD) therapies have limited efficacy. Given that Aβ, a protein that accumulates in the brain of AD patients, has been shown to impair synaptic plasticity and memory, major efforts are ongoing to decrease Aβ load. However, the normal physiological roles of amyloid-β precursor protein (APP), its fragments and processing enzymes might present a problem in providing effective and safe approaches to AD therapy. We have therefore explored a different strategy using targets at the downstream level of Aβ accumulation. In studies of the mechanisms underlying Aβ-induced dysfunction of synaptic plasticity and memory we have defined a central role for cAMP response element (CRE)-dependent gene expression, which is mediated by the transcription factor CRE binding protein (CREB). We have demonstrated that CREB phosphorylation is reduced during induction of synaptic plasticity and memory in the presence of high Aβ levels. Consistent with these observations, up-regulation of both the adenylyl cyclase-cAMP-PKA pathway and the NO synthase-guanylyl cyclase-cGMP-PKG pathway, two enzymatic cascades that are known to increase CREB phosphorylation, rescued the Aβ-induced defects in memory and its electrophysiological correlate, long-term potentiation (LTP). Most importantly, from a drug discovery point of view, two targets, the cAMP degrading enzyme phosphodiesterase- (PDE) 4, and the cGMP degrading enzyme PDE-5, have provided very encouraging data strongly supporting the possibility of using PDE4 and PDE5 inhibitors in order to enhance activation of PKA and PKG, two kinases phosphorylating CREB. Using a SAR approach, we have synthesized a novel compound, JFOA1, with high potency, excellent selectivity for PDE5 over other PDE isoforms, blood brain barrier permeable and safe up to 2 g/kg in acute toxicity test. The compound also showed both ex vivo and in vivo efficacy, as it ameliorated LTP in hippocampal slices treated with Aβ and memory in mice infused with Aβ. Because of these findings, we propose using PDE inhibitors as AD therapeutics.

Neuroprotective Strategies: BDNF and NGF

Barbara Hempstead, MD, PhD, Weill Cornell Medical College

Neurotrophins, including NGF and BDNF are central to many facets of CNS function, with critical roles in neuronal differentiation, dendritic arborization, synaptogenesis and activity-dependent forms of synaptic plasticity. BDNF has pleiotropic effects on synaptic activity that underlie circuit formation and cognitive function. The regulatory mechanisms that permit rapid and dynamic refinement of BDNF action in neurons, particularly during aging or following pathological insult, will be considered. In addition, the distinct actions of NGF and its precursor form, proNGF will be discussed. NGF critically regulates the survival and morphology of cholinergic neurons, and strategies to augment NGF following CNS injury have been considered for neuroprotection. However, proNGF is induced following injury or in Alzheimer's disease, and may mediate neuronal death or dysfunction. Multiple strategies that may act to limit proNGF action, and promote NGF function are considered as potential therapeutic targets for future development.

Dysregulation of Lipid Signaling in Alzheimer's Disease

Gilbert Di Paolo, PhD, The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University

Lipid-mediated signaling regulates a plethora of physiological processes, including critical aspects of brain and synaptic function. In addition, dysregulation of lipid pathways has been implicated in a growing number of neurodegenerative disorders, such as Alzheimer's disease (AD). Although much attention has been given to the link between cholesterol and AD pathogenesis, growing evidence suggests that other lipids, such as phosphoinositides and phosphatidic acid, as well as the enzymes controlling their metabolism (e.g., synaptojanin and phospholipase D, resp.), play an important role. Because regulators of lipid metabolism (e.g. statins) are a highly successful class of marketed drugs, exploration of lipid dysregulation in AD and identification of novel therapeutic agents acting through relevant lipid pathways offers new and effective options for the treatment of synaptic dysfunction in this devastating disorder. In this respect, the use of "lipidomics," an unbiased systems based approach relying on mass spectrometry and allowing for the quantification of hundreds of lipids (including low abundance signaling lipids), is an important step forward, as highlighted in this presentation.

Aß Oligomer Binding to Post-Synaptic Prion Protein Activates Fyn to Mediate Neuronal Dysfunction

Stephen M. Strittmatter, MD, PhD, Yale University School of Medicine

Amyloid-beta (Aß) peptide oligomers are thought to trigger Alzheimer’s disease (AD) pathophysiology. Cellular Prion protein (PrP-C) selectively binds oligomeric Aß assemblies and mediates many AD-related phenotypes. Here, we examined the specificity, the distribution and the signal transduction of Aß/PrP complexes. PrP-C is enriched in post-synaptic densities, and Aß/PrPC interaction leads to Fyn kinase activation. Particular Aß assemblies derived from human AD brain interact with PrP-C and induce Fyn activation. Aß engagement of PrP-C/Fyn signaling yields phosphorylation of the NR2B subunit of NMDA-receptors, which is coupled to an initial increase and then loss of surface NMDA-receptors. Aß-induced LDH release and dendritic spine loss require both PrP-C and Fyn, and AD transgene-induced epileptiform discharges do not occur in mice lacking PrP-C expression. These results delineate an Aß oligomer signal transduction pathway requiring PrP-C and Fyn to alter synaptic function with relevance to AD.

Targeting Mitochondrial-derived ROS to Reverse Synaptic Plasticity and Memory Impairments in Alzheimer's Disease

Eric Klann, PhD, Center for Neural Science, New York University

Generation of reactive oxygen species (ROS) causes cellular oxidative damage and has been implicated in the etiology of Alzheimer's disease (AD). We have shown that decreasing the level of superoxide through the overexpression of mitochondrial superoxide dismutase (SOD-2) prevents memory deficits in the Tg2576 mouse model of AD. Consistent with these findings, we recently demonstrated that AD-related LTP impairments could be prevented when ROS generation from mitochondria was diminished either pharmacologically or via genetic manipulation by the overexpression of SOD-2. In wild-type hippocampal slices treated with exogenous amyloid β peptide (Aβ1-42) and in slices from APP/PS1 mutant mice that model AD, LTP impairments were observed that were prevented by MitoQ, a mitochondria-targeted antioxidant, and EUK134, an SOD and catalase mimetic. Moreover, live staining with MitoSOX Red, a mitochondrial superoxide indicator, combined with confocal microscopy, revealed that Aβ-induced superoxide production could be blunted by MitoQ, in agreement with our electrophysiological findings. Finally, in transgenic mice overexpressing SOD-2, Aβ-induced LTP impairments and superoxide generation were prevented. Taken together, our findings suggest a causal relationship between mitochondrial ROS and Aβ-induced impairments in hippocampal synaptic plasticity and memory. Finally, our findings suggest that mitochondrial-derived ROS are a reasonable therapeutic target for the treatment of memory dysfunction in AD patients.

Targeting Gamma-Secretase Activating Protein for Alzheimer’s Disease

Lawrence P. Wennogle, PhD, Intra-Cellular Therapeutics

In collaboration with Paul Greengard and Rockefeller University, we reported (Nature 467: 95, 2010) the identification of a novel target for drug discovery Gamma-Secretase Activating Protein (GSAP). GSAP participates in the formation of amyloid beta through the interaction with amyloid precursor protein (APP) and gamma-secretase. It is able to impart substrate specificity to the promiscuous protease gamma-secretase at the level of substrate presentation of APP. Importantly, GSAP does not affect NOTCH cleavage. Intra-Cellular Therapies is developing novel therapeutic agents to treat disease progression of Alzheimer’s disease. Agents have been identified that interact with GSAP to limit amyloid beta formation. Novel therapeutic agents for Alzheimer’s disease are currently being developed that represent distinct chemical classes devoid of off-target activity and displaying good oral bioavailability.

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