Epigenetics of Alzheimer's Disease

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Epigenetics of Alzheimer's Disease

Wednesday, September 28, 2011

The New York Academy of Sciences

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The burgeoning increase in the aging population is leading to an increase in the number of patients with common disorders of older adults such as Alzheimer's disease. Although some polymorphisms and risk factors have been associated with both sporadic and familiar forms of Alzheimer's disease, the precise manner by which the environment influences neurodegeneration in these disorders is still unclear. The purpose of this symposium is to discuss the most updated knowledge on the contribution of epigenetic modifications in the initiation and progress of Alzheimer's disease with the goal of advancing basic knowledge and identifying new areas for therapeutic interventions.

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Agenda


1:00 PM

Opening Remarks
Sonya Dougal, PhD, The New York Academy of Sciences
Ottavio Arancio, MD, PhD, Columbia University Medical Center

1:15 PM

Enhancing Histone Acetyl Transferase Activity as a Therapeutic for Alzheimer’s Disease
Yitshak Francis, PhD, Columbia University Medical Center

1:45 PM

Epigenetic Mechanisms Regulating Memory Formation in Health and Disease
Li-Huei Tsai, PhD, Massachusetts Institute of Technology

2:15 PM

Epigenetic Mechanisms in Memory Formation
J. David Sweatt, PhD, University of Alabama at Birmingham

2:45 PM

Coffee Break

3:15 PM

DNA Methylation and Alzheimer's Disease in Humans
Paul D. Coleman, PhD, Sun Health Research Center

3:45 PM

Epigenetics of Alzheimer's Disease
Benjamin Tycko, MD, PhD, Columbia University

4:15 PM

Panel Discussion
Moderated by Cecilia Marta, PhD, Sanofi-Aventis

A 1-hour networking reception will follow the symposium.

Speakers

Organizers

Ottavio Arancio, MD, PhD

Columbia University Medical School

Dr. Ottavio Arancio received his Ph.D and M.D. 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 "bigthink.com".

Cecilia Marta, PhD

Sanofi-Aventis

Cecilia Marta obtained her PhD in Neuroscience from the University of Buenos Aires Argentina in 2000 working on the neuroimmune interactions of neurodegenerative disorders. She then continue her work as a postdoctoral fellow and then Assistant Professor at the University of Connecticut Health Center focusing on the neurodegenerative aspects of Multiple Sclerosis. In late 2005, she joined the CNS Department of Sanofi-Aventis to conduct drug discovery in the area of Multiple Sclerosis. In the beginning of 2010, she joined the newly formed Therapeutic Strategic Unit of Aging within Sanofi in which today she is part of the Translational Medicine team. Neurodegenerative disorders such as Alzheimer's and Parkinson's are part of the current strategic focus of the Unit.

Sonya Dougal, PhD

New York Academy of Sciences

Speakers

Paul D. Coleman, PhD

Sun Health Research Center

Paul Coleman received his undergraduate degree from Tufts (magna cum laude) and his Ph.D. from the University of Rochester. After a tour at the Army Medical Research Laboratory and a faculty position at Tufts he had a Special Fellowship at Johns Hopkins, working with Vernon Mountcastle and David Bodian. He then spent five years on the faculty at the University of Maryland School of Medicine, followed by more than 30 years as Professor in Neurobiology and Anatomy at the University of Rochester. During this time he spent portions of two summers at Cold Spring Harbor Laboratories, receiving training in molecular neurobiology, the latter summer with Jim Eberwine. He is now Professor Emeritus at the University of Rochester, Senior Scientist and Co-Director of Alzheimer Research at Banner Sun Health Research Institute. He is also Editor-in-Chief of “Neurobiology of Aging”.

J. David Sweatt, PhD

University of Alabama at Birmingham

J. David Sweatt obtained his B.S. in Chemistry from the University of South Alabama before attending Vanderbilt University, where he was awarded a Ph.D. for studies of intracellular signaling mechanisms. He then did a post-doctoral Fellowship at the Columbia University Center for Neurobiology and Behavior, working on memory mechanisms in the laboratory of Nobel laureate Eric Kandel. From 1989 to 2006 he was a member of the Neuroscience faculty at Baylor College of Medicine in Houston, Texas, rising through the ranks there to Professor and Director of the Neuroscience Ph.D. program.

Dr. Sweatt’s laboratory studies biochemical mechanisms of learning and memory. In addition, his research program also investigates mechanisms of learning and memory disorders, such as mental retardation and aging-related memory dysfunction. He is currently the Evelyn F. McKnight endowed Chairman of the Department of Neurobiology at UAB Medical School, and the Director of the Evelyn F. McKnight Brain Institute at the University of Alabama in Birmingham. He also is a Professor the Departments of Molecular Physiology and Biophysics, Genetics, and Psychology at UAB.

From 1998 until 2002 he attended drawing and painting classes at the Glassell School of Art of the Museum of Fine Arts, Houston. As an artist he explores the use of painting as a medium for expressing topics of interest in contemporary biomedical research. In 2009 he published a textbook, Mechanisms of Memory, which is illustrated with original paintings and describes current models for the molecular and cellular basis of memory formation.

Li-Huei Tsai, PhD

Massachusetts Institute of Technology

Li-­‐Huei Tsai is the director of the Picower Institute for Learning and Memory at the Massachusetts Institute of Technology and a Picower Professor of Neuroscience. She is also a Principal Investigator in the Howard Hughes Medical Institute and the director of the Neurobiology Program at the Stanley Center for Psychiatric Research at the Broad Institute. Dr. Tsai received a PhD in microbiology at the University of Texas Southwestern Medical Center. She completed postdoctoral fellowships at Cold Spring Harbor Laboratory and the Massachusetts General Hospital. She became an Assistant Professor in the Department of Pathology at Harvard Medical School and, in 1997, she became an Investigator of the Howard Hughes Medical Institute. In 2006, Dr. Tsai became a Picower Professor of Neuroscience at the Massachusetts Institute of Technology (MIT) and became the Director of the Picower Institute for Learning and Memory in 2009. Dr. Tsai’s work has aimed to elucidate the cellular and molecular mechanisms that contribute to the development and manifestation of the pathology and symptoms of Alzheimer’s disease. Recently, Dr. Tsai’s laboratory has revealed that alternations of the epigenetic landscape can benefit cognition in Alzheimer’s disease animal models, even after severe neurodegeneration has occurred. These findings promise chromatin modifying enzymes to be potential targets for treatment of Alzheimer’s disease.

Benjamin Tycko, MD, PhD

Columbia University

Dr. Tycko is a Professor of Pathology and member of the Institute for Cancer Genetics at Columbia University. His work over the past two decades has centered on the role of DNA methylation in human development and disease. This work started with identification of human imprinted genes and their roles in Wilms tumor and Beckwith-Wiedemann syndrome and has continued with recent discoveries of altered epigenetic patterns in cancer-associated stromal cells. The most recent work from the Tycko lab has dealt with the epigenetics of Down syndrome and Alzheimer’s disease. Recent publications on human genetics and epigenetics from Dr. Tycko’s laboratory have appeared in basic and clinical journals including Nature Genetics, PLOS Genetics, Cancer Research and JAMA, and he is an author of the chapter on Epigenetics in the fifth and current edition of Emery and Rimoin’s Principles and Practice of Medical Genetics.

Yitshak Francis, PhD

Columbia University Medical Center

Yitshak Francis (PhD) is an Associate Research Scientist at the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University. Dr. Francis completed his undergraduate degree at the Technion - Israel Institute of Technology where he graduated with honors. He obtained his PhD in Medical Molecular Biology from University College London, researching the role of epigenetics in Alzheimer’s disease under the direction of Professor David Latchman, renowned for his work in the field of transcription factors. During his work at Columbia University, Dr. Francis focused primarily on epigenetic changes triggered in Alzheimer’s disease. His research has led to the identification of novel epigenetics-modifying drugs. For his work Dr. Francis recently won the New Investigator research grant from the Alzheimer Association

Sponsors

For sponsorship opportunities please contact Carmen McCaffery at cmccaffery@nyas.org or 212.298.8642.

The Brain Dysfunction Discussion Group is proudly supported by:

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Abstracts

Enhancing Histone Acetyl Transferase Activity as a Therapeutic for Alzheimer's Disease
Yitshak Francis, PhD, Columbia University Medical Center

Amyloid-beta (Aβ) is a peptide that plays a key role in the development of Alzheimer's disease (AD). Aβ has been found to inhibit memory and its electrophysiological model, long-term potentiation (LTP). A mechanism by which Aβ impairs memory is represented by changes in histone acetylation. Histones are components of the chromatin structure that regulate DNA accessibility for transcription factors leading to memory formation. Notably, histone acetylation has been found to be reduced in vivo following the exposure to high amounts of amyloid-beta. The main strategy that is currently used to up-regulate histone acetylation involves HDAC inhibitors. However, the pleiotropic effect of nonspecific HDAC inhibition may hamper their therapeutic potential. Activators of histone acetyltransferase (HAT) might constitute an alternative avenue to enhance histone acetylation. To this end, we have designed and synthesized a novel HAT activator, YF2, which is soluble, membrane permeable, blood-brain barrier permeable, and with a favorable toxicity profile. In vitro, YF2 shows good affinity for CBP, p300, and PCAF, a lower affinity for GCN5 and no interference with Tip60 or HDACs activity. Additionally, YF2 increases hippocampus acetylation of histone lysines that are involved in memory formation and rescues the defect in histones acetylation levels due to increase in Aβ levels in the hippocampus. Importantly, we found that YF2 rescues the defects in long-term potentiation as well as reference and associative memory in Aβ-depositing transgenic mice and in mice infused with oligomeric Aβ42. Taken together, these results suggest that HAT upregulation might be beneficial against synaptic and memory dysfunctions following Aβ elevation.
 

Epigenetic Mechanisms Regulating Memory Formation in Health and Disease
Li-Huei Tsai, PhD, Massachusetts Institute of Technology

Chromatin modifications, particularly histone-tail acetylation, have recently been implicated in memory formation. Increases inhistone-tail acetylation that are induced by inhibitors of histone deacetylases (HDACis) facilitate learning and memory in wildtype mice as well as in mouse models of Alzheimer's-like neurodegeneration. Moreover, increases in histone acetylation by HDACi treatment induce dendritic sprouting and increase synapse numbers. Long-lasting remodeling of neural circuits, therefore,may underlie the beneficial effects of HDACis on cognition. Through a combination of genetic and pharmacological approaches, we have identified histone deacetylase 2 (HDAC2) to bea major HDAC involved in regulating synaptic plasticity and memory formation. HDAC2-deficient mice exhibit facilitated long-term potentiation (LTP), whereas HDAC2 overexpressingmice exhibit impaired learning and hippocampal LTP. Moreover, HDAC2-deficient mice are refractory to the beneficial effects of HDACis in enhancing cognition. Recently, we found that HDAC2 is dysregulated in mouse models of Alzheimer's disease as well as in Alzheimer's disease human postmortem brains. We propose a model whereby HDAC2 dysregulation causes an epigenetic blockade of gene expression that contributes to cognitive impairment in neurodegenerative diseases such as Alzheimer's. These observations suggestthat targeting chromatin remodeling may serve as a new avenue for treating cognitive decline caused by neurodegeneration.
 

Epigenetic Mechanisms in Memory Formation
J. David Sweatt, PhD, Department of Neurobiology, UAB School of Medicine

This presentation will address the idea that conservation of epigenetic mechanisms for information storage represents a unifying model in biology, with epigenetic mechanisms being utilized for cellular memory at levels from behavioral memory to development to cellular differentiation. Do epigenetic mechanisms operate in behavioral memory formation? We have generated several lines of evidence that support this idea. 1. Contextual fear conditioning triggers alterations in hippocampal histone acetylation, and contextual latent inhibition training triggers similar but distinct changes in histone acetylation. 2. Histone DeAcetylase inhibitors boost memory capacity in rodent memory models and restore long-term memory function in genetically engineered mouse models of Alzhemier's Disease. The methyl-DNA binding protein MeCP2 (the Rett mental retardation syndrome gene product) alters chromatin structure and regulates hippocampal LTP and memory formation. 3. Inhibitors of DNA methylation block both hippocampal LTP and associative learning in vivo. 4. Remote contextual fear memory is associated with persisting changes in DNA methylation in the Anterior Cingulate Cortex, and DNMT inhibition can reverse established remote memory. Thus, an emerging idea is that the regulation of chromatin structure, mechanistically via histone modification and DNA methylation, may mediate long-lasting behavioral change and learning and memory. We find this idea fascinating because similar mechanisms are used for triggering and storing long-term "memory" at the cellular level, for example when cells differentiate.
 

DNA Methylation and Alzheimer's Disease in Humans
Paul D. Coleman, PhD, Sun Health Research Center

Increasing knowledge of epigenetic modifications associated with Alzheimer's disease goes hand in hand with information about altered intracellular locations of epigenetic molecules in Alzheimer's disease. This presentation will provide evidence that transport of selected epigenetic molecules from the cytoplasm into the nucleus is impaired in Alzheimer's disease.
 

Epigenetics of Alzheimer's Disease
Benjamin Tycko, MD, PhD, Columbia University

Our project funded by the NIH Epigenomics Roadmap deals with epigenomic aspects of Alzheimer's disease (AD). One of our aims is to map changes in DNA methylation in brain cells in cases of AD. We are using several methods, including methylation-sensitive Pyrosequencing, promoter methylation analysis on Illumina Infinium arrays, and immunostaining for me-C. In our data so far we find that alterations in net (global) DNA methylation in AD neurons are subtle and occur, at most, in late stages of the disease. However, there appear to be a small set of genes that have altered patterns of CpG methylation specifically in AD neurons. More dramatically, we find that neuronal DNA methylation patterns differ substantially across distinct neocortical regions in the human brain, suggesting a major role for DNA methylation in neuronal specification. We are currently following up these findings on region-specific and disease-specific CpG methylation for specific interesting genes.
 

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