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Alzheimer's Disease and Tau: Pathogenic Mechanisms and Therapeutic Approaches

Alzheimer's Disease and Tau: Pathogenic Mechanisms and Therapeutic Approaches

Friday, September 18, 2015

The New York Academy of Sciences

Presented By


The Microtubule Associated Protein tau (MAPT or tau) is closely linked to Alzheimer's disease (AD), the Fronto-Temporal Dementias (FTDs) and several other neurodegenerative diseases. While it has long been recognized that tau aggregates to form neurofibrillary tangles (NFTs), a hallmark pathological lesion in AD and other disorders, emerging evidence demonstrates that tau has a mechanistically complex role in neurodegeneration. Speakers at this symposium will address novel tau-centered mechanisms of neurodegeneration and new therapeutic approaches for many devastating neurological disorders.

*Reception to follow.

This event will also be broadcast as a webinar; registration is required.

Please note: Transmission of presentations via the webinar is subject to individual consent by the speakers. Therefore, we cannot guarantee that every speaker's presentation will be broadcast in full via the webinar. To access all speakers' presentations in full, we invite you to attend the live event in New York City when possible.

Registration and Webinar Pricing

Member (Student / Postdoc / Resident / Fellow)$15
Nonmember (Academia)$65
Nonmember (Corporate)$85
Nonmember (Non-profit)$65
Nonmember (Student / Postdoc / Resident / Fellow)$45


The Brain Dysfunction Discussion Group is proudly supported by

  • Acorda Therapeutics


* Presentation titles and times are subject to change.

September 18, 2015

8:30 AM

Registration and Continental Breakfast

9:00 AM

Welcome and Opening Remarks
Sonya Dougal, PhD, The New York Academy of Sciences
Robert L. Martone, St. Jude Children’s Research Hospital

9:15 AM

Etiopathogenesis of Hyperphosphorylation of Tau and Potential Therapeutic Targets
Khalid Iqbal, PhD, New York State Institute for Basic Research in Developmental Disabilities

9:45 AM

Amyloid-β and Tau: the Trigger and Bullet for Alzheimer's Disease Pathogenesis
George S. Bloom, PhD, University of Virginia

10:15 AM

Networking Coffee Break

10:45 AM

Microglia: A Reintroduction
Richard M. Ransohoff, MD, Biogen

11:15 AM

Regulation of Tau Secretion
Nicole Leclerc, PhD, Université de Montréal

11:45 AM

Insights into Human Tau Pathology from the Prion Model
Marc I. Diamond, MD, University of Texas Southwestern Medical Center

12:15 PM

Networking Lunch Break and Poster Session

All poster presenters should stand by their posters 12:45–1:45 pm

1:45 PM

Tau Pathology Spreading and Propagation
Michael Hutton, PhD, Eli Lilly and Company
(* The 1:45 pm slides will not be broadcast as part of the live webinar.)

2:15 PM

Monoclonal Antibodies as Therapies for Tau Pathology
Peter Davies, PhD, Feinstein Institute for Medical Research

2:45 PM

Networking Coffee Break

3:15 PM

Cistauosis: A Common Early Disease Mechanism in Alzheimer’s and Traumatic Brain Injury that can be Blocked by Antibody
Kun Ping Lu, MD, PhD, Harvard Medical School

3:45 PM

Development of PET Imaging Biomarkers for PHF-Tau: [18F]-T807 and [18F]-T808
Hartmuth C. Kolb, PhD, Johnson & Johnson, Janssen R&D

4:15 PM

26S Proteasome Dysfunction and Cognitive Impairment Caused by Aggregated Tau Accumulation can be Attenuated by PKA-Mediated Phosphorylation of Proteasomes
Natura Myeku, PhD, Taub Institute for Alzheimer's Disease Research, Columbia University

4:30 PM

TAU Cleavage to Aggregation Prone Fragments: Therapeutic Effects of cAMP and IU1
Magdalena J. Kiprowska, MS, Hunter College and Graduate Center, CUNY

4:45 PM

Closing Remarks
Robert L. Martone, St. Jude Children’s Research Hospital

5:00 PM

Networking Reception

6:00 PM




Robert L. Martone

St. Jude Children's Research Hospital

Robert Martone conducts biomarker research and development with a focus on neuro-oncology in the Department of Pathology at St. Jude Children's Research Hospital.  He was previously 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.

Sonya Dougal, PhD

The New York Academy of Sciences


George S. Bloom, PhD

University of Virginia

George Bloom moved to the University of Virginia in August, 2000, after spending 16 years at the University of Texas Southwestern Medical Center at Dallas, where he left as a Professor in the Department of Cell Biology. He is currently a Professor in both the College of Arts and Sciences (Department of Biology) and the School of Medicine (Department of Cell Biology). His alma mater, the University of Pennsylvania, awarded him a B.A. in Biology and History in 1973, and a PhD in Biology in 1979. Dr. Bloom’s career originally focused on fundamental cell biological questions, most notably how mammalian cells move and change shape, and transport cellular building blocks from place to place within the cell. Recently, this basic science approach led directly to more clinically relevant research on Alzheimer’s disease, which is now the dominant theme in his lab. He has served on grant review panels for the NIH, the Alzheimer's Association, the American Cancer Society and the Department of Defense, and is currently an Associate Editor for the journal Cytoskeleton.

Peter Davies, PhD

Feinstein Institute for Medical Research

Peter Davies received a BSc and a PhD from the University of Leeds, England. He was a post-doctoral fellow in the Department of Pharmacology at the University of Edinburgh, Scotland before joining the staff of the Medical Research Council in Edinburgh in 1974, where he began his research on Alzheimer’s disease. In 1977, he moved to Albert Einstein College of Medicine in the Bronx, and became the Scientific Director of the Litwin/Zucker Center for Research on Alzheimer’s disease at the Feinstein Institute for Medical Research, North Shore/LIJ in 2006. Dr. Davies research has been focused on biochemistry of Alzheimer's disease. He has published about 300 papers, and has been interested in the development of new treatments and diagnostic tests for Alzheimer's disease. He has received numerous awards for his research, including a Lifetime Achievement Award from the International Congress on Alzheimer’s Disease (ICAD), the first Metropolitan Life Foundation Prize and the Potamkin Prize. Dr. Davies has received two MERIT awards from the National Institutes of Health.

Marc I. Diamond, MD

University of Texas Southwestern Medical Center

Marc Diamond, MD, is the founding Director of the Center for Alzheimer’s and Neurodegenerative Diseases, and is a Professor of Neurology and Neurotherapeutics. Dr. Diamond completed an internship, residency, and chief residency in neurology at the University of California, San Francisco (UCSF) in 1997. After a postdoctoral fellowship, he was a faculty member in the Neurology Department at UCSF from 2002-2009. From 2009-2014 he was the David Clayson Professor of Neurology at Washington University in St. Louis, before he was recruited to UT Southwestern. His research focuses on molecular mechanisms of neurodegeneration in Alzheimer’s disease and related disorders, with the goal of developing novel therapies and diagnostic tools. A therapeutic antibody he co-developed at Washington University in St. Louis is now entering clinical trials for treatment of dementia. The Center for Alzheimer’s and Neurodegenerative Diseases is comprised of a multidisciplinary group of investigators who are focused on understanding the basis of progressive protein aggregation in human disease. They are using this knowledge to hasten the day when neurodegeneration can be detected presymptomatically and stopped before it causes disability.

Michael Hutton, PhD

Eli Lilly and Company

Michael Hutton joined Eli Lilly as Chief Scientific Officer for Neurodegenerative Disease in 2009 and was appointed UK Site Scientific Leader in 2012.  He is based at Lilly’s Research Centre in Surrey, England and leads drug discovery for Alzheimer’s Disease, Parkinson’s Disease and Fronto-temporal Dementia.  Eli Lilly’s Alzheimer’s program has delivered multiple drug candidates to clinical development including an anti-amyloid antibody (solanezumab) that was recently reported to slow cognitive decline in mild AD in Phase 3 and BACE1 inhibitors.  Prior to joining Lilly, Dr Hutton worked at Merck (2yrs) and at the Mayo Clinic Jacksonville (11yrs).  During his time at Mayo, Dr Hutton’s team played a major role in determining the causes of Fronto-temporal Dementia with the discovery mutations in tau and progranulin and the mechanism by which these lead to neurodegeneration.  He received the Potamkin and Metlife Prizes for his work on Alzheimer’s Disease and Fronto-temporal Dementia.  Dr Hutton has published over 200 papers in peer reviewed journals and is a regular speaker at international conferences on Alzheimer’s Disease and related neurodegenerative conditions.

Khalid Iqbal, PhD

New York State Institute for Basic Research in Developmental Disabilities

Khalid Iqbal, Professor and Chairman, Department of Neurochemistry at the New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, received his PhD in Biochemistry in 1969 from the University of Edinburgh, UK. Dr. Iqbal was the first to describe in 1974 the bulk isolation and protein composition of neurofibrillary tangles/paired helical filaments (PHF) from Alzheimer disease brains. In 1986 he, along with Dr. Inge Grundke-Iqbal, discovered that the PHF protein and the microtubule-associated protein tau are the same and that tau in PHF is hyperphosphorylated. Dr. Iqbal is the recipient of many prestigious honors and awards, including the Potamkin Prize for Alzheimer Disease Research from the American Academy of Neurology, and the Zenith Award from Alzheimer’s Association, USA. He founded and chaired the biennial International Conference on Alzheimer’s Disease from 1988 to 2008. In 2008 Alzheimer’s Association, USA established a Khalid Iqbal Lifetime Achievement Award for Alzheimer’s Disease Research, which is given out annually at the Alzheimer’s Conference to a senior established researcher. Dr. Iqbal has authored over 300 scientific papers and edited seven books on research advances in Alzheimer disease and related neurodegenerative disorders. He currently serves on the editorial boards of several journals.

Magdalena J. Kiprowska, MS

Hunter College and Graduate Center, CUNY

Magdalena J. Kiprowska is a PhD candidate in Dr. M. Figueiredo-Pereira’s laboratory at Hunter College, CUNY, in New York City. She is originally from Poland where she earned her first degree, MS in Chemistry at the University of Gdansk (2004). Following completion of her studies she worked as a Junior Specialist of Technology at Polpharma S.A., a pharmaceutical company in Poland. She subsequently moved to the United States and earned an MA in Biological Sciences at Hunter College, CUNY (2009). She is currently enrolled in the last semester of the Biochemistry PhD program at Hunter College and Graduate Center, CUNY. Her doctoral research focuses on in vitro and in vivo models of Alzheimer’s disease (AD). She is investigating in rat cerebral cortical neuronal cultures the impact of downregulating the deubiquinating enzyme Usp14 on protein degradation by the proteasome, as a means to prevent protein aggregation relevant to AD. Moreover, she is developing a new mouse model of AD using prostaglandin J2 as a neurotoxic product of cyclooxygenases. This PGJ2-induced mouse model provides a strategy to investigate the role of neuroinflammation on the progression of AD, and to evaluate novel anti-inflammatory drugs for therapeutic intervention in AD.

Hartmuth C. Kolb, PhD

Johnson & Johnson, Janssen R&D

Dr. Hartmuth Kolb received his PhD in Organic Chemistry in 1991 at Imperial College of Science, Technology and Medicine, London UK. Following postdoctoral work with K. Barry Sharpless (2001 Chemistry Novel Laureate), he joined Ciba-Geigy in 1993. In 1997, Dr. Kolb became the Head of Chemistry at Coelacanth Corporation. In this role, he and Dr. Sharpless developed the Click Chemistry approach to drug discovery. In 2002, he joined The Scripps Research Institute as an Associate Professor, focusing on in situ Click Chemistry. From 2004 to 2013, he was the head of the Siemens Biomarker Research group, where he and his team developed novel oncology and neurodegenerative disease PET tracers, a key highlight being the PHF-Tau tracer, [18F]-T807. Dr. Kolb joined Johnson & Johnson in January 2014 as the Head of Neuroscience Biomarkers. He is an author on over 75 peer-reviewed publications and review articles.

Nicole Leclerc, PhD

Université de Montréal

Nicole Leclerc is Full Professor at the Université de Montréal. She completed her PhD at Laval University in the laboratory of Dr. Richard Hawkes where she examined the development of the anatomical and functional parasagittal zonation of the rat cerebellar cortex. For her first post-doctoral training, she joined the laboratory of Dr. Karl Herrup at Harvard University where she further characterized the molecular organization of the cerebellar cortex. She did a second post-doctoral training in the laboratory of Dr. Ken Kosik at Harvard University where she examined the contribution of MAP2, a microtubule-associated protein, to the elaboration of the dendritic arborization. In 1994, she joined the Department of Pathology and Cell Biology at the Université de Montréal where she started her laboratory and continued to characterize the contribution of MAP2 to dendritic differentiation. In recent years, her laboratory has focused on the contribution of tau pathology to the process of neurodegeneration observed in Alzheimer’s brain. Her laboratory investigates the mechanisms involved in the propagation of tau pathology in the brain. The main goal of her research is to identify the pathways involved in the secretion of tau to abrogate the propagation of tau pathology in the brain.

Kun Ping Lu, MD, PhD

Harvard Medical School

Kun Ping Lu, MD, PhD, received his medical training in China and PhD degree from Duke University, followed by postdoctoral training at Salk Institute, where he cloned Pin1, before becoming as an independent investigator at Harvard. Currently, Dr. Lu is Professor of Medicine at Harvard Medical School and Chief, Division of Translational Therapeutics at Beth Israel Deaconess Medical Center. His lab has discovered that Pin1-catalyzed cis-trans conformational regulation after phosphorylation is a unique signaling mechanism that has the pivotal but opposite effects on the development of cancer and Alzheimer’s disease, two major disease that were rarely studied together before. Importantly, this new disease mechanism may lead to novel diagnostic and therapeutic procedures. Notably, his lab has recently identified Pin1 inhibitors for treating cancer and autoimmune disorders, and developed antibodies specifically against the cis P-tau conformation for early diagnosis and treatment of Alzheimer’s disease and traumatic brain injury.

Natura Myeku, PhD

Taub Institute for Alzheimer's Disease Research, Columbia University

Natura Myeku is an associate research scientist in Dr. Karen Duff’s laboratory at Columbia University in the Taub Institute for Alzheimer’s disease. She received her PhD from the Graduate Center CUNY in 2011. Dr. Myeku was a post-doctoral fellow in the laboratory of Dr. Karen Duff where she studied the impact of accumulated tau species on the Ubiquitin Proteasome Pathway (UPS). In her first years as an independent investigator she studied dysfunction of synaptic proteasomes in relation to tauopathy disorder. Myeku is also interested in translational science and in parallel she is investigating mechanisms to activate proteasome function as a means to reduce aberrant tau accumulation as a novel therapy for AD and other tauopathy disorders.

Richard M. Ransohoff, MD


Dr. Ransohoff graduated with honors from Bard College, Annandale, NY with a BA in Literature, and received the MD degree with honors from Case School of Medicine, Cleveland, OH. He completed residencies in Internal Medicine (Mt. Sinai Medical Center, Cleveland, OH; Board Certified 1981) and Neurology (CCF; Board Certified 1985). From 1984 to 1989, Dr. Ransohoff was a post-doctoral fellow in the laboratory of Dr. Timothy Nilsen, Dept. of Molecular Biology and Microbiology, Case School of Medicine. He served at the Cleveland Clinic (Cleveland, OH) as Staff Neurologist (1984-2014) at the Mellen Center for MS Treatment and Research and was recognized (1996-2014) in the ‘Best Doctors’ compendium for his expertise in clinical care of MS patients. He was Staff Scientist in the Departments of Molecular Biology (1989-1999) and Neuroscience (1999-2014) and Director of the Neuroinflammation Research Center (2005-2014) of the Cleveland Clinic’s Lerner Research Institute. From 2014 he has been VP and Senior Research Fellow, Neuroimmunology at Biogen in Cambridge, MA. He lists more than 380 PubMed entries. Dr. Ransohoff is a member of the American Academy of Neurology (AAN), a Fellow of the American Neurological Association (ANA) and of the American Association for the Advancement of Science and a member of the Association of American Physicians. Dr. Ransohoff has served on NIH and National MS Society Study Sections, as journal editor and editorial board member (J. Immunology; Neurology; J. Neuroimmunology; Nature Reviews Immunology; Trends Immunology; Neurology: N2) and as organizer for Keystone Symposia (Neuroinflammation: 2015, 2017; Microglia: 2016). Among other honors, Dr. Ransohoff delivered the ANA Bennett Lecture (2009) and was awarded the John Dystel Prize of the AAN and National MS Society (2012). He is a member of the SAB of the Gladstone Institute for Neurological Disorders and a member of the Senate of the DZNE (German Center for Neurodegenerative Disease).


Bronze Sponsors



Grant Support

This program is supported in part by an educational grant from Merck and Co., Inc.

Promotional Partners

The Alzheimer's Drug Discovery Foundation

The Dana Foundation


The Brain Dysfunction Discussion Group is proudly supported by

  • Acorda Therapeutics


Etiopathogenesis of Hyperphosphorylation of Tau and Potential Therapeutic Targets
Khalid Iqbal, PhD, New York State Institute for Basic Research in Developmental Disabilities

Alzheimer’s disease (AD) is a multifactorial disorder. However, independent of the etiology, AD is histopathologically characterized by the presence of numerous neurofibrillary tangles of abnormally hyperphosphorylated tau and Aβ core-neuritic (senile) plaques. The tangles and not Aβ plaques are required for the clinical expression of the disease, the dementia. Besides AD, hyperphosphorylated tau is also a hallmark of a family of neurodegenerative disorders called tauopathies. The activity of protein phosphatase-2A (PP2A), which is the major regulator of phosphorylation of tau, is compromised in the brains of cases with AD, Down syndrome and Guam amyotrophic lateral sclerosis Parkinsonism dementia complex (Guam ALSPD). My lab has been conducting research on finding how hyperphosphorylated tau can lead to neurodegeneration and how different etiological factors can lead to tau pathology. In my talk I will discuss our studies that show the possible molecular mechanisms by which hyperphosphorylation of tau may be involved in neurodegeneration in different tauopathies, and what therapeutic opportunities are available based on these findings.

Amyloid-β and Tau: the Trigger and Bullet for Alzheimer’s Disease Pathogenesis
George S. Bloom, PhD, University of Virginia

The most conspicuous histopathological features of Alzheimer’s disease (AD) brain include two types of poorly soluble aggregates: extracellular amyloid plaques made from amyloid-β (Aβ) peptides and intraneuronal neurofibrillary tangles assembled from the neuron-specific protein, tau. The behavioral symptoms of AD result from synaptic dysfunction among neurons that mediate memory and cognition, and the death of those neurons. Growing evidence indicates that soluble forms of Aβ and tau work together, independently of their accumulation into plaques and tangles, to drive healthy neurons into the diseased state, and that trademark toxic properties of Aβ require tau. One example of tau-dependent Aβ toxicity is ectopic cell cycle re-entry (CCR) of neurons, which ironically leads to neuron death and may account for as much as 90% of neuron death in AD. Brain insulin resistance is also an AD hallmark and potentially fundamental driver of AD symptoms, but the mechanisms by which it causes the synaptic dysfunction and neuron death that underlie memory and cognitive impairment had remained unknown. We now demonstrate that CCR follows Aβ oligomer (AβO) induced activation of mechanistic target of rapamycin complex 1 (mTORC1) at the plasma membrane and mTORC1-dependent tau phosphorylation, and is blocked in cultured neurons by lysosomal mTORC1 activation by insulin. Because AβOs also cause neuronal insulin resistance, our data suggest that AβOs dysregulate normal mTOR signaling by activating mTORC1 at the cell surface while preventing insulin from stimulating lysosomal mTORC1. These dual effects of AβOs provide a mechanistic basis for classifying AD as type 3 diabetes.

Microglia: A Reintroduction
Richard M. Ransohoff, MD, VP and Senior Research Fellow, Neuroimmunology and Adjunct Professor of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University

Microglia arise during primitive hematopoiesis and initially enter the developing murine brain around E10.5, before other glia and prior to neuronal differentiation. During development, microglia interact extensively with neurons, helping to establish neuronal populations through influences on survival, apoptosis and corpse-clearance. As neuron-to-neuron contacts are forming during early postnatal life, microglia refine neuronal network properties by synaptic pruning.
Neuron-microglial and microglial-neuron dialogs are mediated by contact-dependent and soluble signals. As one example, fractalkine (CX3CL1) is a transmembrane chemokine expressed in the CNS solely by neurons, which also release soluble fractalkine to signal at a distance. The fractalkine receptor (CX3CR1) is restricted to microglia among CNS cells. Perturbation of fractalkine/fractalkine receptor signaling results in altered microglial function, with consequences observed from mid-gestation through aging and neurodegeneration. Using mice deficient for fractalkine or its receptor provides a wealth of insights into microglial function in the intact CNS and may have direct clinical relevance, given a common hypomorphic CX3CR1 allele in humans. Examination of the mechanism underlying fractalkine regulation of microglial responses may yield information useful for translating model results to clinical application.

Regulation of Tau Secretion
Nicole Leclerc, PhD, Université de Montréal

Recent studies have demonstrated that human tau protein can be secreted by neurons, an event linked to the propagation of tau pathology in Alzheimer brain. We recently examined whether tau secretion by cortical neurons would be modified upon insults. Both starvation and inhibition of lysosomal function, two insults known to take place in Alzheimer’s disease, significantly increased tau secretion. However, the most important increase of tau secretion was observed when both insults were superimposed. In such conditions, the pattern of tau secretion differed from that of control neurons. As a result of these treatments, at least two tau species were released. Furthermore, in all conditions tested, an important pool of secreted tau was dephosphorylated. Collectively, our results demonstrate that insults such as nutrient deprivation and lysosomal dysfunction observed in neurodegenerative diseases could result in an increase of tau secretion and propagation of tau pathology in the brain. The question to be answered is whether the different tau species that are released by neurons exert distinct toxic effects and/or whether they contribute distinctly to the propagation of tau pathology. It is crucial to unravel the distinct contribution of tau species to these events to develop therapeutic strategies to prevent tau-induced neuronal dysfunction and to abrogate the spreading of tau pathology in Alzheimer brain.

Insights Into Human Tau Pathology from the Prion Model
Marc I. Diamond, MD, University of Texas Southwestern Medical Center

Neurodegenerative diseases linked to protein amyloids could be caused by trans-cellular propagation of protein aggregates. In this model, protein assemblies escape a cell, enter a vulnerable cell, and create new pathology by acting as a template, or "seed," for further aggregation. Prion diseases progress by this mechanism. To quantify seeding activity, and to test the role of proteopathic seeds in the development of pathology, we have developed a FRET-based biosensor cell assay that quantifies seeding activity. This identifies seeds in human and mouse brain far in advance of standard histopathology. Prion diseases have tremendous clinical and neuropathological diversity that has been linked to specific amyloid structures, or "strains," which replicate faithfully over decades in animal hosts. Like prionopathies, tauopathies are clinically and neuropathologically heterogeneous, and feature intraneuronal accumulation of tau amyloid assemblies that are rich in beta sheet structure. We have described essential strain characteristics of tau prions, in which unique conformations propagate indefinitely in cells and in animals, and create unique patterns of neuropathology. We have linked human tauopathies to distinct groups of tau prion strains. We find that after intracerebral inoculation, strain conformation defines the structural and biochemical properties of the induced aggregates, neuronal pathology, and patterns of spread. Our results suggest a very proximal role for proteopathic seeds in the pathogenesis of tauopathies, with unique strains determining patterns of pathology and clinical phenotype. We hypothesize this could ultimately enable syndromic classification of tauopathies based entirely on aggregate structure.
Coauthors: Sarah K. Kaufman1,2, Jennifer L. Furman1, PhD, Kelly Del Tredici, MD, PhD3, Heiko Braak, MD3, Ann C. McKee, MD4, Nigel J. Cairns, PhD5, Lea T. Grinberg, MD, PhD6, William Seeley, MD6
1 Center for Alzheimer's and Neurodegenerative Diseases, University of Texas, Southwestern Medical Center, Dallas, Texas, United States
2 Program in Neuroscience, Washington University in St. Louis School of Medicine, St. Louis, Missouri, United States
3 Department of Neurology, University of Ulm, Germany
4 Department of Neurology and Pathology Boston University School of Medicine Boston, Massachusetts, United States
5 Department of Neurology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, United States
6 Department of Neurology, UCSF, San Francisco, California, United States


Tau Pathology Spreading and Propagation
Michael Hutton, Eli Lilly and Co Ltd

Neurofibrillary pathology composed of the microtubule associated protein tau is a characteristic feature of Alzheimer’s Disease as well as multiple rare tauopathies such as FTLD-tau and Progressive Supranuclear Palsy. In each case, the density and distribution of the tau lesions correlates with the extent of neuronal loss and with the clinical progression of the disorder. Moreover multiple mutations in the tau (MAPT) gene have been shown to cause FTD linked to chromosome 17 establishing that tau dysfunction is sufficient to cause neurodegeneration. These mutations impact tau in different ways but significantly all are predicted to enhance tau aggregation suggesting that protein misfolding is a critical component of the neurodegenerative cascade. More recently, research from several laboratories has suggested, both in vitro and in vivo, that misfolded tau proteins can be released from neurons at synaptic terminals and can then enter recipient cells. The misfolded tau is then able to template its structure onto endogenous tau leading to seeded tau aggregation and the resultant propagation of neurofibrillary pathology. However, despite considerable research in this area over the past 5 years significant uncertainty remains regarding the mechanism of tau pathology spreading and the tau species involved in this process. To address these questions, we have established multiple cell-based and in vivo models that have allowed us to examine both the process of tau pathology spreading and the tau species involved. These studies have demonstrated that, in these model systems, tau pathology appears to spread only through anatomically connected regions and that large tau assemblies are required for spreading, templating and pathology propagation in vivo. Characterization of the various tau species that underpin propagation in our model suggests that the most efficient structures are short filaments that contain hyperphosphorylated tau proteins.

Monoclonal Antibodies as Therapies for Tau Pathology
Peter Davies, PhD, Litwin-Zucker Center for Research on Alzheimer’s Disease, Feinstein Institute for Medical Research

Monoclonal antibodies are increasingly popular therapeutics, although applications to diseases of the central nervous system have been limited. Targeting extracellular deposits of  beta-amyloid with specific antibodies appeared to be an attractive idea, but the notion that the intracellular deposits of tau that make up the neurofibrillary tangles of Alzheimer’s disease and related disorders could also be targets for antibody therapy seemed very speculative. However, numerous such studies are now underway, and it seems probable that human testing of such therapy is imminent.
Unlike the situation with beta-amyloid, which has a limited number of antibody epitopes to target, the 441 amino acids of tau, plus numerous post-translational modifications and conformational changes provide an almost unlimited number of potential targets for monoclonal antibodies. Tau sequence, conformational and phosphoepitope antibodies have all been tested in mouse models. It is not yet clear which type of antibody shows the most consistent efficacy in mice, although experience suggests that differences between these classes might be dependent on dosage.
The issue of how antibodies to an intracellular pathology can be efficacious is still controversial. Most mechanistic studies assume contact between antibody and target in the extracellular space. Once bound to antibody, there are two routes for removal of tau: sequestration and degradation by glial cells through antibody Fc receptors, and exit from CNS into the circulation. Recent results suggest that CNS-derived tau does appear in blood after treatment with some antibodies, but do not exclude glial-mediated clearance, which seems almost certain.
Supported by NIA R37 AG022102

Cistauosis: A Common Early Disease Mechanism in Alzheimer’s and Traumatic Brain Injury that can Be Blocked by Antibody
Kun Ping Lu, MD, PhD1

A major neuropathological hallmark of Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE) is tangles made of phosphorylated tau (P-tau). A major environmental risk factor for these diseases is traumatic brain injury (TBI), but tauopathy is not detectable acutely or subacutely after TBI. Therefore, how TBI leads to tauopathy and how to stop it are still unknown. We identify a unique proline isomerase, Pin1 that inhibits tauopathy development in AD by converting P-tau from cis to trans. By creating antibodies able to distinguish these two P-tau conformations, we discover that cis P-tau is an early pathogenic tau conformation leading to tauopathy and memory loss in AD and a novel drug target (Cell 2012, 149: 232). We further extend these studies to TBI and find robust cis p-tau after sport- and military-related TBI in humans and mice. Acutely after TBI in mice and stress in vitro, neurons prominently produce cis p-tau, which disrupts axonal microtubule network and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, termed “cistauosis”, appears long before other tauopathy, and is effectively blocked by cis P-tau antibody, but enhanced by trans antibody. Treating TBI mice with cis antibody not only blocks early cistauosis, but also effectively prevents TBI-related widespread tauopathy and neuronal loss, as well as behavioral and psychological defects (Nature 2015, 523: 431). Thus, cistauosis is a common early disease mechanisms in TBI, AD and CTE, and cis antibody may be further developed for early diagnosis and treatment of these devastating diseases.
Coauthors: Asami Kondo, PhD1, Koorosh Shahpasand, PhD1, Onder Albayram, PhD1, Yu-Min Lin, PhD1, Rebekah Mannix, MD2, William Meehan, MD2, and Xiao Zhen Zhou, MD1
1 Division of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massuchussetts, United States
2 Micheli Center for Sports Injury Prevention, Children’s Hospital Boston, Harvard Medical School, Boston, Massuchussetts, United States


Development of PET Imaging Biomarkers for PHF-Tau: [18F]-T807 and [18F]-T808
Hartmuth C. Kolb, PhD, Johnson & Johnson, Janssen R&D

Background: There are two main neuropathologic hallmarks in Alzheimer’s Disease (AD), senile neuritic plaques containing ß-amyloid protein, and neurofibrillar protein aggregates containing hyperphosphorylated tau protein.
Methods: We have developed PET imaging agents for these pathological hallmarks, using a competitive autoradiography assay based on human AD brain sections. Brain uptake of [F18]-labeled tracers was measured in rodents and non-human primates. First in human studies were conducted to compare tracer uptake and retention with the established Braak staging patterns of tau pathology in AD.
Results: We have discovered several novel, small molecule tau binding compounds that show high selectivity for native tau aggregates in human AD brain sections over β-amyloid. The most promising compounds, [18F]-T807 and [18F]-T808, have a high brain uptake/fast clearance in rodents and primates. White matter distribution is very low. First in human studies revealed good agreement with Braak staging.
Conclusions: We have identified several small heterocyclic compounds that bind to human PHF-tau. In vitro and in vivo studies confirm that the lead candidates [F18]-T807 and T808 bind to PHF-tau selectively over β-amyloid, show good PK and metabolic properties, and exhibit excellent brain uptake/washout kinetics in rodents, non-human primates and in humans, in agreement with the known Tau pathology in AD.
Disclaimer: This work was conducted at Siemens MI, Biomarker Research. The Tau imaging assets now belong to Avid Radiopharmaceuticals. T807 (AV-1451) is an investigational drug. The presentation is not sanctioned and/or endorsed by Avid/Lilly or Johnson & Johnson.

26S Proteasome Dysfunction and Cognitive Impairment Caused by Aggregated Tau Accumulation can be Attenuated by PKA-Mediated Phosphorylation of Proteasomes
Natura Myeku, PhD1

The ubiquitin proteasome system (UPS) selectively degrades misfolded proteins including those implicated in the pathogenesis of neurodegenerative diseases. We investigated the effects of abnormal tau accumulation on proteasome function in the brains of a mouse model of tauopathy and in a cross to a UPS reporter mouse (line Ub-G76V-GFP). Accumulation of insoluble tau correlated with a progressive decrease in the peptidase activity of brain 26S proteasomes, while levels of ubiquitinated proteins and undegraded Ub-G76V-GFP increased. After affinity purification, the 26S proteasomes from mice with tauopathy were less active in hydrolyzing ubiquitinated proteins, small peptides (by the 20S core particle), and ATP (by the 19S ATPases). Tau was physically associated with these defective proteasomes, and 26S proteasomes from normal mice incubated with oligomers or fibrils generated from recombinant tau displayed less hydrolyzing capacity for ubiquitinated proteins, peptides, and ATP.  The loss of proteasome activity was attenuated by administering an agent which activates cAMP/PKA signaling and proteasome subunit phosphorylation. Enhancing proteasome function led to reduced levels of aggregated tau and improved cognitive performance in early stages of tauopathy. Thus, proteasome function and proteolysis by the UPS decreases with worsening tauopathy, and stimulating proteasome activity through cAMP/PKA is a promising therapeutic strategy.
Coauthor: Karen E. Duff PhD1
1 Department of Pathology and Cell Biology, Taub Institute for Alzheimer's Disease Research, Columbia University, New York, NY, USA

TAU Cleavage to Aggregation Prone Fragments: Therapeutic Effects of cAMP and IU1
Magdalena Kiprowska, MS (PhD soon)1

TAU is a highly soluble protein. Under non-pathological conditions TAU is turned over by the ubiquitin/proteasome pathway (UPP) and the autophagy/lysosome pathway. In brains of AD patients, TAU accumulates as aggregates in neurofibrillary tangles (NFTs). One of the critical aspects of TAU pathology is its abnormal cleavage causing it to switch from a soluble monomer to a non-soluble form characteristic of NFTs. This abnormal TAU cleavage occurs early in the development of TAU pathology. The conditions that cause TAU to be cleaved to oligomerization- and aggregation-prone fragments are poorly established. We demonstrate in rat primary cerebral cortical neuronal cultures that impairment of the UPP and mitochondria trigger caspase and calpain activation respectively, leading to TAU cleavage to aggregation-prone fragments. These data are important since UPP and mitochondrial dysfunction occur early in AD pathogenesis. The dual vulnerability of TAU to caspase and calpain cleavage needs to be addressed therapeutically to maintain TAU integrity and prevent TAU pathology. We focused on preserving UPP and mitochondrial function. Increasing neuronal cAMP levels does both, while IU1 potentially stimulates degradation via the UPP by selectively inhibiting the de-ubiquitinating enzyme Usp14. Our results demonstrate that raising cAMP levels with the lipophilic peptide PACAP27 rescues TAU cleavage and neuronal viability, while IU1 does not. We established that IU1 inhibits mitochondrial function and E1-dependent ubiquitin activation. These data support the use of PACAP27 as a novel therapeutic strategy to preserve TAU integrity and prevent TAU cleavage, oligomerization and aggregation relevant to Alzheimer’s disease.
Coauthors: Maria Figueiredo-Pereira, PhD1
1 Hunter College and Graduate Center, CUNY, New York, New York, United States

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