A Truce in the BAP-tist/Tau-ist War? Progress Toward A Unified Understanding of Alzheimer's Disease

A Truce in the BAP-tist/Tau-ist War? Progress Toward A Unified Understanding of Alzheimer's Disease

Tuesday, December 10, 2013

The New York Academy of Sciences

Presented By

 

Alzheimer's disease is a public health crisis that will grow to devastating proportions over the next several decades unless effective therapies are found. Two hallmark pathologies in the brain have characterized the disease since it was first described over 100 years ago by Alois Alzheimer. The first is the neuritic plaque, a fibrillar structure composed largely of the beta-amyloid peptide (or BAP) surrounded by dystrophic neurites, activated macrophages, and reactive astrocytes. The second is the neurofibrillary tangle, consisting of neuronal inclusions of the microtubule-associated protein tau in a highly fibrillar form. For most of the history of Alzheimer's research, these structures and their associated biologies have been studied in relative isolation. Vigorous debates as to which pathology is more relevant to disease has in addition led to what has been referred to as the 'BAP-tist/Tau-ist' wars, further isolating these biologies. As many of the front-line therapies designed to test 'the amyloid hypothesis' are reaching the clinic and failing to show efficacy, the research community is reconsidering some of the prevailing dogmas and seeking to better integrate our understanding of Alzheimer's disease biology and how it unfolds during aging. The goal of this symposium is to revisit the old BAP-tist/Tau-ist schism and ask whether two fields of research on one disease can offer each other mechanistic clues in the quest to find effective therapies.

*Reception to follow.

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The Biochemical Pharmacology Discussion Group is proudly supported by



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Mission Partner support for the Frontiers of Science program provided by Pfizer

Agenda

* Presentation titles and times are subject to change.


December 10, 2013

8:30 AM

Registration and continental breakfast

9:00 AM

Welcome and Introduction
Jennifer Henry, PhD, The New York Academy of Sciences
Robert B. Nelson, PhD, Lundbeck Research USA

9:10 AM

Tau Reduction: Killing Two Birds with One Stone
Lennart Mucke, MD, Gladstone Institute of Neurological Disease

9:50 AM

Breaking the Code of Amyloid-β Oligomers
Sylvain E. Lesné, PhD, MSc, University of Minnesota

10:30 AM

Coffee break

11:00 AM

The CAMKK2-AMPK Kinase Pathway Mediates the Synaptotoxic Effect of Amyloid-β in Part Through Tau Phosphorylation
Franck Polleux, PhD, Columbia University

11:40 AM

PAR-1/MARK Kinases as Therapeutic Targets for Alzheimer’s Disease and Related Tauopathies
Bingwei Lu, PhD, Stanford University School of Medicine

12:20 PM

Lunch break

1:20 PM

Abeta and Tau Interactions: Lessons from Animal Models
Frank M. LaFerla, PhD, University of California, Irvine

2:00 PM

Harnessing Innate Immunity against Alzheimer's Disease
Terrence Town, PhD, University of Southern California

2:40 PM

Coffee break

3:10 PM

Inflammation in Alzheimer’s Disease
Tony Wyss-Coray, PhD, Stanford University School of Medicine

3:50 PM

AD-Gene Driven Lysosomal Dysfunction links Tau and Amyloid Pathologies and Neurodegeneration
Ralph A. Nixon, MD, PhD, Nathan Kline Institute

4:30 PM

Networking reception

5:30 PM

Close

Speakers

Organizers

Ken Jones, PhD

Forest Research Institute

Ken is a Senior Clinical Scientist in the Department of Psychiatry at Forest Research Institute, the research subsidiary of Forests Labs, the New York based Pharmaceutical company. He has over 20 years of preclinical drug discovery and clinical development experience in the area of CNS disorders. Ken received his PhD in Physiology at Rutgers University studying neuronal networks that control stereotypical behaviors of model organisms. During postdoctoral training at Harvard Medical School with Robert Baughman he developed mammalian primary cell culture techniques to map NMDA and AMPA receptors at synaptic and extrasynaptic sites. His subsequent contributions to drug research include the deorphanization of several G-protein-coupled receptors, including the elucidation of the dimeric nature of GABAB receptors, and the co-discovery of a non-visual photoreceptor that regulates circadian rhythms. Prior to joining Forest, Ken ran several early-stage drug development projects in psychiatry at Lundbeck Research USA.

Robert Martone

Covance Biomarker Center of Excellence

Robert Martone is Neuroscience Therapeutic Area Lead for the Covance Biomarker Center of Excellence. He has extensive experience in the pharmaceutical industry leading neuroscience drug discovery and technology teams through all phases of discovery from target identification through clinical trials with expertise in both small molecule and protein therapeutics. He also has several years of academic research experience in molecular neurobiology, with a focus on the molecular genetics of familial neuropathies, and CNS tumor biomarker development.

Robert B. Nelson, PhD

Lundbeck Research USA

Bob Nelson is a Research Fellow at Lundbeck Research USA in Paramus, NJ, where he heads the Neuroinflammation-1 disease biology unit. The goal of this group is to design novel therapeutics based on understanding the intersection between innate immune mechanisms, cerebrovascular inflammation, and central pathology in Alzheimer's and other neurological disorders. Prior to joining Lundbeck in 2010, Bob was a research investigator at Pfizer and overall has 23 years of experience in the pharmaceutical industry. Bob received his doctorate from Northwestern Univ. in 1987 (under Aryeh Routtenberg) followed by post-doctoral fellowships at DuPont (under Robert Siman) at Harvard Med School (under Huntington Potter).

Jennifer Henry, PhD

The New York Academy of Sciences

Speakers

Frank M. LaFerla, PhD

University of California, Irvine

Professor Frank LaFerla’s research is focused on understanding the pathogenesis of Alzheimer disease, the most common form of dementia among the elderly. His lab has developed several transgenic mouse models of neurodegenerative disorders including the 3xTg-AD mice, which recapitulate the two major neuropathological lesions, plaques and tangles. This model has been widely distributed to researchers throughout the USA and over 20 countries throughout the world. A major research focus of his lab is to understand the relationship between Aß and tau pathology and how each affects the development of the other. Dr. LaFerla is chair of the Department of Neurobiology and Behavior and Director of the Institute for Memory Impairments and Neurological Disorders (UCI MIND).  He has received several honors for his research accomplishments including the Ruth Salta Junior Investigator Achievement Award from the American Health Assistance Foundation, Zenith Fellows Award from the Alzheimer Association, UCI Chancellor’s Professorship, Distinguished Mid-career Faculty Research Award, Promising Work Award from the Metropolitan Life Foundation for Medical Research, and was elected as a Fellow to the American Association for the Advancement of Science.

Sylvain E. Lesné, PhD, MSc

University of Minnesota

Dr. Lesné grew up in Luc-sur-mer, a tiny village in Basse-Normandie, France and attended college at the Université de Caen, Basse-Normandie where he graduated with a Master's degree in Biochemistry (major in Neuroscience) and a PhD in Molecular and Cellular Biology (major in Neuroscience). He joined Dr. Karen H. Ashe's laboratory at the University of Minnesota in November 2002 as a postdoctoral research associate and then moved on to becoming a research associate 2 years later. In December 2009, Dr. Lesné was recruited by the N. Bud Grossman Center for Memory Research and Care as an Institute for Translational Neuroscience Scholar and as tenure-track Assistant Professor in the Department of Neuroscience at the University of Minnesota. Dr. Lesné's group is focused on understanding the molecular and cellular mechanisms triggered by proteins abnormally aggregating in cerebral brain tissues during the course of neurodegenerative disorders, with a specific focus on Alzheimer's disease.

Bingwei Lu, PhD

Stanford University School of Medicine

Bingwei Lu received his BS degree from Fudan University, Shanghai, China, and his PhD degree from Cornell University, Ithaca, NY. He conducted postdoctoral research at the University of California San Francisco and Howard Hughes Medical Institute in the labs of Yuh Nung Jan and Lily Jan. He started his independent academic career as Head of Laboratory of Developmental Neurobiology at Rockefeller University and later moved to his current position as Associate Professor in the Department of Pathology at Stanford University School of Medicine. His laboratory uses Drosophila and mouse models and patient-derived cells to try to understand how the diverse neuronal cell types are generated and properly maintained in the nervous system and how defects in neuronal development and maintenance may contribute to the pathogenesis of devastating brain disorders such as brain tumors and neurodegenerative diseases.

Lennart Mucke, MD

Gladstone Institute of Neurological Disease

Ralph A. Nixon, MD, PhD

Nathan Kline Institute

Franck Polleux, PhD

Columbia University

Dr Polleux did his undergraduate and graduate studies at Université Claude Bernard in Lyon, (France) where he obtained his Ph.D. in Neuroscience in 1997. He then joined the laboratory of Dr Anirvan Ghosh at Johns Hopkins University for his post-doctoral training. In 2002, Dr Polleux was hired as an Assistant Professor in the Neuroscience Center and Department of Pharmacology at University of North Carolina- Chapel Hill where he became an Associate Professor in 2008. In August 2010, he joined The Scripps Research Institute in La Jolla, California. In November 2013, he was recruited by the Department of Neuroscience at Columbia University to join the new Mind, Brain, Behavior Institute. Throughout his career, Dr Polleux has focused on the identification of the molecular mechanisms underlying neuronal development in the mammalian brain. More recently, his lab also started studying the signaling pathways underlying synaptic loss during early stages of Alzheimer's Disease progression.

Terrence Town, PhD

University of Southern California

Dr. Town's primary focus has been to develop and mechanistically interrogate genetic models of neurologic disorders, with a specific interest in the immune system and inflammation as related to Alzheimer disease (AD). He has experience in the fields of innate immunology, neurobiology, and inflammation, with specific expertise in both in vivo and in vitro models of neuroimmune and neuroinflammatory aspects of AD and other neurodegenerative disorders. The primary goal of his group is to translate basic science discoveries into potential therapies for these devastating disorders of the mind. Despite considerable work in this area, many important questions remain concerning the nature and timing of immune/inflammatory responses in the context of AD, and at what point and how to therapeutically intervene.

Tony Wyss-Coray, PhD

Stanford University School of Medicine

Tony Wyss-Coray, PhD is a professor of neurology at Stanford University School of Medicine and a senior research career scientist at the Veterans Administration Palo Alto Health Care System. He received a PhD in immunology in 1992 from the University of Berne, Switzerland and trained in neurobiology at The Scripps Research Institute and The Gladstone Institute of Neurological Disease. Wyss-Coray studies the role of immune and injury responses in brain aging and neurodegeneration, pursuing the hypothesis that failing or dysfunctional immune responses underlie or contribute to the demise of the aging brain. He combines the study of mouse models with human clinical samples using cytomic, proteomic, and bioinformatic tools. He is the recipient of an NIH Director's Transformative Research Award, a Zenith award from the Alzheimer's Association, a distinguished scholar award from the John Douglas French Alzheimer Foundation, and he is an inventor on multiple patents.

Sponsors

Academy Friends

Covance

Lundbeck Research USA

Grant Support

This program is supported in part by an educational grant from AstraZeneca.

Promotional Partners

Alzheimer Research Forum

The Dana Foundation

The Lancet Neurology

Nature

Scientific American Mind

Society for Neuroscience


The Biochemical Pharmacology Discussion Group is proudly supported by



  • WilmerHale

Mission Partner support for the Frontiers of Science program provided by Pfizer

Abstracts

Abeta and Tau Interactions: Lessons from Animal Models
Frank. M. LaFerla, PhD, University of California, Irvine

Aß and tau pathology accumulate in selective regions of the Alzheimer’s disease brain. Using a transgenic approach, we generated several genetically-modified mice to study the interactions between these two critical pathological proteins. Using both genetic and pharmacological approaches, we are elucidating the molecular pathways by which Aß and tau influence the onset and progression of each other, and how they impact synaptic biology. Our studies provide critical in vivo evidence for a strong mechanistic link between soluble Aβ, wild-type tau and synaptic pathology, and suggest that targeting mechanisms to increase Aβ and tau clearance early in the disease process could have therapeutic benefit in preventing cognitive decline.
 

Breaking the Code of Amyloid-β Oligomers
Sylvain E. Lesné, PhD, MSc, University of Minnesota

Departing from the original postulates that defined various neurodegenerative disorders, accumulating evidence supports a major role for soluble forms of amyloid proteins as initiator toxins in Alzheimer's disease, Parkinson's disease, frontotemporal dementias, and prion diseases. Soluble multimeric assemblies of amyloid-β (Aβ), tau, α-synuclein, and the prion protein are generally englobed under the term oligomers.
 
Due to their biophysical properties, soluble amyloid oligomers can adopt multiple conformations and sizes that potentially confer differential biological activities. Therein lies the problem: with sporadic knowledge and limited tools to identify, characterize, and study amyloid oligomers, how can we solve the enigma of their respective role(s) in the pathogenesis of neurodegenerative disorders? To further our understanding of these devastating diseases, the code of the amyloid oligomers must be broken.
 
In this talk, I will present evidence demonstrating that not all Aβ oligomers induce the same changes on tau to mediate their effects, highlighting the importance to consider each Aβ assembly in its proper context.
 

PAR-1/MARK kinases as therapeutic targets for Alzheimer's disease (AD) and related tauopathies
Bingwei Lu, PhD, Stanford University School of Medicine

Despite decades of intensive research, no treatment is available that can prevent or halt AD and related tauopathies. Current treatments only modify the symptoms, leaving the root cause of the disease unaltered. Moreover, the recent failures of several highly publicized clinical trials indicate that current drug development approaches at the Big Pharma and biotech companies may be flawed, and that novel approaches to AD drug development are urgently needed. Abnormal phosphorylation and aggregation of tau is a pathological hallmark of a number of neurological disorders. In AD, tau abnormality has emerged as a major pathogenic event downstream of APP/Aβ, the leading candidates for causative agents of AD. However, the signaling events linking APP/Aβ and tau are poorly defined. Studies in Drosophila and mammalian cells by our lab and others have shown that PAR-1/MARK kinases critically regulate the phosphorylation of tau and mediate the toxicity of APP/Aβ, in part by triggering a sequential phosphorylation event that generates hyper-phosphorylated, pathogenic tau. Unique among tau kinases, PAR-1/MARK kinases also phosphorylate Dlg/PSD-95, a master regulator of postsynaptic structure and function and whose expression and synaptic localization are disrupted early on in AD. Supporting the relevance of PAR-1/MARK kinases in AD-related disease pathogenesis, their phosphorylation and activation respond to APP/Aβ. These studies thus identify a neuronal signaling pathway triggered by APP/Aβ that impinges on PAR-1/MARK to impact synaptic function through distinct kinase substrates, including tau and PSD-95. Importantly, we showed that inhibition of MARK using a peptide inhibitor (MKI) effectively blocks the synaptic and dendritic toxicity of Aβ-42 in primary cultures of rat hippocampal neurons. These results strongly support the relevance of Drosophila models to the understanding of AD pathogenesis and identify PAR-1/MARK kinase as a critical player and promising therapeutic target in AD. More recently, in genetic screens for modifiers of PAR-1/MARK-induced neurotoxicity, we uncovered a novel mechanism of PAR-1/MARK regulation involving its degradation by the SCF(Slimb) E3 ubiquitin ligase, whose action is antagonized by the fat facets (FAF)/USP-9x deubiquitinating enzyme. FAF/USP-9x positively regulates the stability of PAR-1/MARK and thus represents a new drug target. In Drosophila models, inhibition of FAF offers protection against Aβ-induced synaptic toxicity. These newly identified modifiers of PAR-1/MARK stability thus offer new therapeutic targets for combating AD and related tauopathies.
 

Harnessing Innate Immunity against Alzheimer's Disease
Terrence Town, PhD, University of Southern California

Few topics in the field of Alzheimer's disease (AD) research have brought about the level of excitement and interest as the role of innate immunity and inflammation in the pathobiology and potential treatment of the disease. My group has utilized transgenic AD model rodents and cell culture approaches to explore the role of key regulators of inflammation and innate immunity in pathologic mechanisms of disease at the brain-immune interface. Our hypothesis is that ‘re-balancing’ inflammation by activating innate immunity to promote ‘good’ neuroinflammation will militate against AD-like pathology. In this presentation, I will share three independent molecular approaches in support of this hypothesis. At the level of peripheral innate immunity, genetic or nanoparticle-based ablation of hematogenous macrophage transforming growth factor-beta (TGF-β)-Smad 2/3 signaling leads to brain recruitment of these cells, restriction of cerebral amyloidosis, and functional recovery. Unleashing cerebral innate immunity by ablating the anti-inflammatory interleukin-10 cytokine, or by releasing inhibition of Toll-like receptor signaling via IRAK-M deletion, prompts microglial remodeling of cerebral amyloid that does not come at the cost of runaway neuroinflammation or bystander neuronal injury.
 

Inflammation in Alzheimer’s disease
Tony Wyss-Coray, PhD, Stanford University School of Medicine

Epidemiological and genetic evidence link Alzheimer’s disease with inflammation and immune responses. The nature of this link is not clearly understood but microglia and the complement pathway appear to be central players. Interestingly, normal aging results in microglial activation and dysfunction and prominent increases in complement factor expression. These observations raise the question whether aging and the associated increase in inflammation are at the heart of sporadic AD and in turn, whether targeting age-associated inflammation would provide a therapeutic approach against the disease. We use a combination of physiological methods to manipulate systemic aging and proteomic methods to try to identify secreted signaling proteins that promote aging or potentially rejuvenate the brain. Our findings point to age-dependent changes in local and systemic immune responses and cellular signaling factors which are sufficient to modulate brain aging and ameliorate neurodegeneration and cognitive deficits associated with aging and models for AD.
 

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