The Biology of Apolipoprotein E

Speakers

Organizers

Kelly Bales, PhD

Pfizer Research & Development

Kelly R. Bales received her BS and MS degrees from Purdue University and completed a PhD in Neuroscience from Indiana University while employed at Eli Lilly where she contributed to drug discovery efforts in the area of Alzheimer's and Parkinson’s disease. In 2008, she moved to the Neuroscience Research Unit at Pfizer Global Research & Development and is currently a Research Fellow in the Neurodegeneration Team. Projects in Kelly's laboratory span the drug discovery chain from novel target identification to support of late stage assets. Currently she and her team are building novel assays to use as screening tools to enable the identification of compounds that modulate apolipoprotein E levels. Additionally she is the biology lead for the early phase gamma secretase modulator program whose goal is to identify small molecule gamma secretase modulators that selective lower brain β-amyloid 42 levels. Kelly is also the lead research representative to the monoclonal antibody program; Ponezumab, that is currently under development for the treatment of AD in the Primary Care Business Unit. Kelly has deep expertise in the area of pre-clinical models of neurodegenerative disorders with specific emphasis on the interaction between the apolipoprotein E and β-amyloid. Kelly has co-authored more than 80 peer-reviewed publications, numerous review articles and invited book chapters. She is also co-inventor on numerous patents related to novel therapies for AD.

Mercedes Beyna, MS

Pfizer Research & Development

Mercedes Beyna is currently a research scientist at Pfizer, where she is using molecular, cellular, genetic, and imaging approaches in the quest to understand the biology underlying autism spectrum disorders. She is passionate about neuroscience and has worked in the field for over 10 years, in both academic and industrial laboratory settings. Mercedes attended Binghamton University, earning her undergraduate degree in Biology, and subsequently received her Master's Degree in Biology from New York University. As an active member of the Biochemical Pharmacology Discussion Group, she enjoys developing interesting and educational symposia.

Roland Staal, PhD

Lundbeck Research USA

Roland Staal received his PhD in Pharmacology from the University of Medicine and Dentistry of NJ with a focus on animal models of Parkinson's disease. He did his post-doctoral studies at Columbia University, where he studied mechanisms of dopamine exocytosis as well as alpha-synuclein and how it affects synaptic vesicle integrity and susceptibility of mice to the Parkinsonian neurotoxin MPTP. Since then, he has worked in industry, studying protein misfolding and protein clearance in neurodegenerative diseases as well as neuroinflammation. Therapeutic strategies that he has worked on include receptor antagonists, enzyme inhibitors, protein aggregation inhibitors as well as immunotherapy. He is currently working at Lundbeck Research in Paramus, NJ in the Neuroinflammation department.

Jennifer Henry, PhD

The New York Academy of Sciences

Speakers

Guojun Bu, PhD

Mayo Clinic

Dr. Bu is a Professor and Consultant in the Department of Neuroscience at Mayo Clinic in Jacksonville. Prior to joining Mayo Clinic in late 2010, he was a Professor at Washington University School of Medicine. He is an acknowledged leader in the field of apoE and its receptors in Alzheimer’s disease. In the early 90s, his research led to the identification of apoE receptor LRP1 as the endocytic receptor for tissue-type plasminogen activator, an enzyme that is clinically used to dissolve blood clots during myocardial infarction and stroke. Dr. Bu has made major contributions to the understanding of LRP1 function in CNS and his seminal work has defined the role of LRP1 in APP trafficking and in brain metabolism of Aβ and apoE. Dr. Bu's current research includes defining the roles of LRP1 in brain lipid metabolism, synaptic functions and in the pathogenesis of AD. His work also focuses on understanding the mechanisms by which apoE4 acts as a strong risk factor for AD. His review in Nature Reviews Neuroscience in 2009 highlighted critical challenges and opportunities in this research area. Dr. Bu serves as an editorial board member for the Journal of Biological Chemistry and Journal of Lipid Research. He is also the Editor-in-Chief for Molecular Neurodegeneration.

Michael Greicius, MD

Stanford University

Dr. Greicius graduated from Amherst College and received his medical degree from Columbia University’s College of Physicians and Surgeons. He completed his neurology residency in the Partners program (Brigham and Women’s Hospital and Massachusetts General Hospital) followed by a joint fellowship in behavioral neurology (UCSF) and functional imaging (Stanford). He is currently an assistant professor of neurology and neurological sciences at Stanford University where he is the medical director of the Stanford Center for Memory Disorders and principal investigator of the Functional Imaging in Neuropsychiatric Disorders (FIND) Lab. Dr. Greicius’ research involves a relatively novel functional MRI (fMRI) approach known as resting-state connectivity. This approach entails measuring temporal correlations in the spontaneous activity of brain regions while a patient rests quietly in the scanner and is capable of detecting a host of distinct brain networks in a single 8-minute scan. Recent work suggests that these distinct functional brain networks are targeted by distinct neurodegenerative disorders. To enhance understanding of these functional networks the lab uses multimodal approaches combining resting-state fMRI with task-activation fMRI, diffusion tensor imaging, structural covariance measures, and, most recently gene expression.

Jungsu Kim, PhD

Washington University School of Medicine

Dr. Kim graduated Summa Cum Laude in 2000 from Pohang University of Science & Technology in South Korea with a bachelor's degree in life science. He received his PhD in 2007 under the guidance of Dr. Todd Golde at Mayo Clinic and further training in the laboratory of Dr. David Holtzman at Washington University. Dr. Kim's laboratory is interested in understading the molecular and celluar basis of neuronal dysfunction in Alzheimer's disease and other common neurodegenrative diseases. One of their research goals is to develop therapeutic strategies targeting brain lipid-regulating proteins, such as ApoE, LDLR, and ABCA1. In addition, his lab uses a combination of genomics, proteomics, and biochemical approaches to identify novel microRNAs involved in neurodegeneration, synaptic plasticity, and brain lipid metabolism.

Steven M. Paul, MD

Weill Cornell Medical College

Steven M. Paul, M.D., is the Director of the Helen and Robert Appel Alzheimer’s Disease Research Institute and Professor of Neuroscience (Neurology) and Psychiatry at Weill Cornell Medical College. He was formerly the Executive Vice President of Science and Technology and President of the Lilly Research Laboratories (LRL) of Eli Lilly and Company. In his role as Lilly’s R&D leader, Dr. Paul led the R&D efforts of over 8,000 LRL scientists and physician investigators with an annual R&D budget of over $4.0 billion. Under Prior to assuming his position at Lilly, Dr. Paul served as Scientific Director of the National Institute of Mental Health (NIMH/NIH) in Bethesda, Maryland.Dr. Paul received his Bachelor of Arts degree, Magna Cum Laude with honors in Biology and Psychology from Tulane University, in 1972. He received his Master of Science degree in Anatomy (Neuroanatomy) and his Doctor of Medicine degree, both in 1975, from the Tulane University School of Medicine. Dr. Paul is licensed to practice medicine in the States of Maryland and Indiana.

Dr. Paul's own research activities have established an important role for specific neurotransmitter receptors in mediating the central actions of various neuroactive drugs. Among his many contributions has been the delineation of the role of receptors for the inhibitory neurotransmitter GABA in mediating the behavioral effects of benzodiazepines, barbiturates, short-chain alcohols as well as a novel class of neuroactive steroids. Despite his administrative responsibilities at Lilly,Dr. Paul worked on several new therapeutic approaches for Alzheimer’s disease, resulting in the discovery of a novel monoclonal antibody (solanezumab) directed at the amyloid ß-peptide which is currently in phase III clinical trials as a potential disease-modifying therapy for Alzheimer’s disease.

G. William Rebeck, PhD

Georgetown University

Bill Rebeck is a Professor of Neuroscience at Georgetown University. He trained as a biochemist at Harvard University, receiving his PhD in 1991. He then spent a year in Germany on a Fulbright Fellowship, working in a molecular biology lab studying Alzheimer’s disease. He returned to Boston and worked for eleven years at Massachusetts General Hospital, establishing his own lab investigating genetic risk factors for Alzheimer’s disease. In 2003, he moved to Georgetown University, where he received tenure in 2006. He has published over 100 peer-reviewed research articles on Alzheimer’s disease and has received continuous laboratory funding from the National Institutes of Health since 1996. He teaches an undergraduate class on synaptic transmission and numerous graduate lectures on neuroanatomy and neurodegeneration. He is currently Professor of Neuroscience, and Director of the Interdisciplinary Program in Neuroscience, which trains the Neuroscience PhD students at Georgetown.

David Riddell, PhD

Pfizer Research & Development

Dr. David Riddell is currently a Research Fellow in the Neurodegeneration Group at Pfizer, Neuroscience, Groton, CT, where he heads a team of 9 scientists targeting APP processing, disease-modifying mechanisms for Alzheimer's Disease, covering both in vitro and in vivo pharmacology. He graduated from the University of St. Andrews, Scotland with a BSc (Hons) in biochemistry and completed his doctorate research on the role of apoE in the development of atherosclerosis at University College London in 1997. In 2000, Dr Riddell joined the department of neurodegeneration research at Glaxosmithkline, where he applied his knowledge of apoE and cholesterol biochemistry to the study of Alzheimer's disease. During this time David also began drug discovery efforts aimed at lowering Aβ levels. In 2004, David joined Wyeth Neuroscience as a Principal Scientist and later, Associate Director running groups aimed at both Aß lowering and novel apoE-related targets related to AD. Although David's primary role is driving drug discovery efforts, his Alzheimer's research has focused on the basic understanding of the physiological role of APP processing and mechanisms by which cholesterol and apoE impact the pathogenesis of this debilitating disease.

Karl H. Weisgraber, PhD

Gladstone Institute of Neurological Disease & University of California, San Francisco

Dr. Weisgraber received a B.A. degree in Zoology and a Ph.D. degree in Organic Chemistry from the University of Connecticut. In 1979, he was one of the founding members of the newly established Gladstone Institute of Cardiovascular Disease. He is currently Senior Investigator in the Gladstone Institute of Cardiovascular Disease and Gladstone Institute of Neurodegenerative Disease and Professor of Pathology at the University of California, San Francisco. His long-standing research interests focus on the structure and function of apolipoprotein E (apoE) in cardiovascular and Alzheimer’s disease. The experimental approach involves the use of x-ray crystallography, site-directed mutagenesis, mouse models, and other methods of biophysical characterization to define differences among the apoE isoforms that are responsible for the differential effects that the isoforms exert in various disease settings. A key structural feature of apoE4 is domain interaction, in which the amino- and carboxyl-terminal domains of apoE interact through arginine-61 and glutamic acid-255. The working hypothesis is that domain interaction is an underlying factor for the detrimental features of apoE4 in neurodegenerative diseases. A mouse model specific for domain interaction displays neurodegeneration and functional and cognitive deficits in the absence of an A beta effect. Associated with these deficits, there is an unfolded protein stress response in astrocytes that leads to astrocyte dysfunction. These results suggest that astrocytes may play a more important role in apoE4-associated neurodegeneration than previously appreciated. Based on the hypothesis that domain interaction contributes to the apoE4 phenotype, a collaboration with Merck used a structure-based drug design approach to identify small molecule drugs that prevent domain interaction in apoE4 with the expectation that these drugs will reduce or eliminate the adverse effects of apoE4.

Cheryl L. Wellington, PhD

University of British Columbia, Vancouver

Dr. Wellington obtained her PhD in Microbiology at the University of British Columbia in 1991 and did postdoctoral training at Harvard Medical School, the University of Calgary, and the University of British Columbia. She joined the Department of Pathology and Laboratory Medicine at the University of British Columbia in 2000 and was promoted to Associate Professor in 2006. Dr. Wellington’s research interests encompass include lipid and lipoprotein metabolism in the brain and how this relates to chronic and acute neurological disorders. Dr. Wellington’s group has made key contributions to the understanding of the role of apolipoprotein E (apoE) in Alzheimer's Disease. ApoE is the major cholesterol carrier in the brain and the best established genetic risk factor for late-onset Alzheimer’s Disease. However, the mechanisms by which apoE affects Alzheimer’s Disease pathogenesis is poorly understood. Dr. Wellington's laboratory has shown that the amount of lipids carried on apoE affects the metabolism of AΒ peptides, which are toxic species that accumulate as amyloid plaques in the brains of patients with Alzheimer’s Disease and also accumulate in individuals who have suffered traumatic brain injury. Specifically, Dr. Wellington has identified the cholesterol transporter ABCA1 as the physiological transporter of lipids onto brain apoE. Her group has shown that mice deficient in ABCA1 have poorly-lipidated apoE in the brain and develop more amyloid, whereas transgenic mice that overexpress ABCA1 have lipid-rich apoE and have virtually no amyloid deposits. Her current research projects are aimed at developing methods to increase apoE lipidation in the brain for application to both Alzheimer’s Disease and traumatic brain injury.