The Biology of Apolipoprotein E

The Biology of Apolipoprotein E

Tuesday, May 24, 2011

The New York Academy of Sciences

Alzheimer's disease (AD) is the most common cause of dementia in the elderly population, with a projected cost of over $100 billion annually in the US alone (www.alzdiscovery.org). Late-onset AD (LOAD), the most common form of the disease, develops after age 60. The e4 allele of the apolipoprotein E (apoE) gene is the most widely reproduced susceptibility allele for LOAD with e4 carriers having an earlier age of disease onset as well as a greater probability of LOAD. Despite the strong genetic association of e4 with LOAD, there are significant gaps in our understanding of how apoE participates in disease pathogenesis, and why this role is differentiated by the various apoE isoforms. Known beneficial roles for apoE in brain include cholesterol transport from astrocytes to neurons for maintenance of  neuronal function and synapse generation. ApoE also mediates the uptake and clearance of the Aß peptides by neurons and astrocytes, and possibly across the BBB.  However, apoE has also been reported to correlate with increase Aß production and aggregation, and is co-deposited in neuritic plaques, a neuropathological hallmark of LOAD. This symposium brings together experts in the field of Aß and ApoE biology as well as brain lipid metabolism to address whether apoE is friEnd or foE in the pathogenesis of LOAD, and to discuss potential therapeutic strategies based on the apoE pathway that may be amenable for the prevention and treatment of LOAD.

Networking reception to follow.

Presented by

Agenda

*Presentation times are subject to change.


8:30 AM

Registration & Continental Breakfast

9:00 AM

Introduction
Kelly R. Bales, PhD, Pfizer Research & Development

9:10 AM

ApoE: FriEnd or FoE, from Mice to Man
Steven M. Paul, MD, Weill Cornell Medical College

9:55 AM

Tracking ApoE Effects from Genotype and Gene Expression to Brain Networks and Behavior
Michael Greicius, MD, Stanford University

10:40 AM

Coffee Break

11:10 AM

Domain Interactions of ApoE in Synaptic Pathology and Cognition
G. William Rebeck, PhD, Georgetown University

12:00 PM

Lunch Break

1:00 PM

ApoE and Its Receptors in Brain Lipid Metabolism and Synaptic Functions
Guojun Bu, PhD, Mayo Clinic

1:45 PM

Astrocytes: An Emerging Role in ApoE4-mediated Alzheimer's Disease
Karl H. Weisgraber, PhD, Gladstone Institute of Neurological Disease & UCSF

2:30 PM

Coffee Break

3:00 PM

Insights into the Regulation of apoE & Aβ Levels in vivo
Jungsu Kim, PhD, Washington University School of Medicine

3:40 PM

The Importance of Apolipoprotein E Function for the Beneficial Effects of LXR Agonists in the Damaged Central Nervous System
Cheryl L. Wellington, PhD, University of British Columbia, Vancouver

4:20 PM

Modulating ApoE3 as a Novel Therapeutic Intervention for the Treatment of AD
David Riddell, PhD, Pfizer Research & Development

5:00 PM

Networking Reception

6:00 PM

Adjourn

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.

Sponsors

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

Academy Friend

Bristol-Myers Squibb Research and Development

Grant Support

This event is funded in part by the Life Technologies™ Foundation.

Promotional Partners

Alzheimer’s Research Forum

Antibodies Online GmbH

The Dana Foundation

Abstracts

ApoE: FriEnd or FoE, from Mice to Man

Steven M. Paul , MD, Weill Cornell Medical College 

The apolipoprotein E alleles are the most important genetic risk factors for late-onset Alzheimer’s disease (AD) with the Ɛ4 allele increasing and the Ɛ2 allele decreasing risk (as well as age of onset) respectively. How these apoE alleles so dramatically alter one’s risk (and age of onset) for developing AD is not completely understood but there is compelling evidence the apoE has multiple actions within the CNS and one (or likely more) of these contribute to its etio-pathophysiological role in AD pathogenesis. Work in our laboratory using transgenic mouse models of AD and targeted replacement human apoE mice has shown that apoE alters the metabolism and clearance of amyloid-β peptides in brain and in an isoform-dependent manner (E2>E3>E4). The latter contributes to the age-dependent and apoE isoform-dependent accrual and deposition of these peptides to form neuritic (amyloid) plaques. Our data on brain amyloid burden in transgenic mice are strikingly reminiscent of recent neuroimaging data in cognitively normal humans carrying different apoE alleles. While these data strongly suggest an important role for apoE in determining brain amyloid burden it is likely apoE plays additional roles in AD pathogenesis. More recent studies in our lab suggest that apoE has amyloid-independent (but isoform-dependent) actions to promote tau aggregation/phosphorylation, an age-dependent seizure phenotypeand even alterations in hippocampal morphology/development. These data will be discussed in the context of novel therapeutic approach to treating or preventing AD.

Tracking ApoE Effects from Genotype and Gene Expression to Brain Networks and Behavior

Michael Greicius, MD, Stanford University 

This talk will consider attempts by our group to understand how the ApoE4 allele increases risk for Alzheimer’s disease (AD). Using a variety of human datasets in healthy control subjects, patients with mild cognitive impairment (MCI), and patients with AD we have established a pipeline of identifying and then validating candidate genes that may interact with ApoE. Focusing on one gene hypothesized to interact with ApoE we will review preliminary results from gene expression data and the ADNI dataset that support this hypothesis. Methods for confirming this association in a resting-state fMRI dataset will also be described. It will be argued that imaging endophenotypes can be used to help build or refute molecular pathways linking ApoE to AD.

ApoE Signaling Pathways in Neurons and Glia

G. William Rebeck, PhD, Georgetown University 

Studies have indicated that APOE genotype affects the level of amyloid in the brains of humans and mouse models of Alzheimer's disease.  These observations, as well in experiments on apoE and Ab clearance or apoE and Ab aggregation, have focused attention on the effects of APOE on AD pathological processes.  We hypothesize that APOE could also affect processes prior to AD pathogenesis, increasing the risk of AD.  To test this hypothesis, we analyzed the brains of APOE knock-in mice, expressing the human APOE alleles from the endogenous mouse APOE promoter, but without any transgenes for amyloid formation.  Golgi staining of these brains revealed that the APOE-e4 mice had significantly fewer dendritic spines in cortical neurons at all ages tested (1 month, 3 months, 1 year).  Cortical neurons from APOE-e4 mice also had the shortest and simplest apical dendrites, compared to APOE-e2 and APOE-e3 mice.  At 15 weeks of age, the APOE-e4 mice had two-three fold higher levels of the NMDA receptor 2B subunit, supporting the model that APOE-e4 affects synaptic function in the absence of AD pathogenesis.  We also examined whether APOE genotype affected glial activation in vivo, based on our earlier work that apoE and an apoE-derived peptide reduced glial inflammation in vitro.  In the APOE knock-in mice, we found no significant differences in the basal number of hippocampal microglia or astrocytes, although there was a trend for increases for both in the APOE-e4 mice (Microglia: APOE-e3 100%, APOE-e2 104%,  APOE-e4 126%; Astrocytes: APOE-e3 100%, APOE-e2 125%, APOE-e4 148%, non-significant).  We are currently examining whether the APOE-e4 mice have increased inflammatory responses to brain insult.  Together these data support a model where APOE-e4 affects neurons and glia early, making the brain more susceptible to AD pathogenesis later in life. 

ApoE and Its Receptors in Brain Lipid Metabolism and Synaptic Functions

Guojun Bu, PhD, Mayo Clinic

Brain lipids such as cholesterol play critical roles in neuronal membrane homeostasis and synaptic functions. However, the mechanisms that govern their biogenesis and transport to neurons are poorly understood. Apolipoprotein E (apoE) is a major lipid transporter in the brain. Of the three human apoE isoforms (E2, E3 and E4), apoE4 is a strong risk factor for late-onset Alzheimer's disease (AD). Brain apoE/lipoprotein particles, produced primarily by astrocytes, deliver cholesterol and other lipids to neurons via apoE receptors, which belong to the low-density lipoprotein receptor (LDLR) family. To ultimately understand why apoE4 is a risk factor for AD, it is essential to study the differential functions of apoE isoforms in brain lipid transport and synaptic functions, and what specific roles apoE receptors play in these processes. We have demonstrated that brain apoE metabolism is mediated by both LDLR and LDLR-related protein 1 (LRP1). However, neuronal deletion of Lrp1, but not Ldlr, impairs cholesterol metabolism in mice. This suggests that LRP1 is the predominant cholesterol transport receptor in neurons. Conditional Lrp1 forebrain knockout (LRP1-KO) mice have decreased brain cholesterol, sulfatide and cerebroside; reduced dendritic spine density and branching; fewer synapses; diminished synaptic functions; neuroinflammation; and eventual neurodegeneration. LRP1-KO mice also have memory deficits and movement disorders consistent with compromised dendritic spine/synaptic integrity and synaptic functions. Because LRP1 levels are reduced in human AD brains, our LRP1-KO mouse model offers an opportunity to study the pathogenic mechanisms of AD. Interestingly, apoE4-targeted replacement (TR) mice also exhibit impaired lipid metabolism and synaptic functions and that apoE4 is less stable compared to apoE3. Together, our results have strong implications on how apoE isoforms differentially regulate brain lipid metabolism and synaptic functions via apoE receptors. We propose that enhancing apoE and apoE receptor-mediated lipid transport in AD brains might be a beneficial strategy to treat AD.

Astrocytes: An Emerging Role in ApoE4-mediated Alzheimer's Disease

Karl H. Weisgraber, PhD, Gladstone Institute of Neurological Disease & UCSF

It is increasing clear that Alzheimer's disease (AD) is a multi-factorial disease and that the amyloid cascade is not the only pathway to the disease. In spite of intensive effort to identify other genes associated with AD, none to date approach the impact of apolipoprotein E4 (apoE4) - 65 to 80% of AD subjects have at least one copy of apoE4. Our studies focus on the contribution of the unique apoE4 structural property, referred to as domain interaction, to neurodegeneration independent of the A beta pathway. In a mouse model specific for domain interaction (Arg-61 apoE model), we demonstrated synaptic, functional, and cognitive deficits associated with this structural property in the absence of A beta. Domain interaction is associated with low levels of brain apoE, resulting from decreased secretion by astrocytes. It appears that domain interaction is recognized and an abnormally folded protein in the ER of astrocytes that causes an unfolded protein stress response. This stress is associated with astrocyte dysfunction that we believe results in ineffective neuronal support that ultimately contributes to neurodegeneration. In recent studies, we have accumulated additional evidence linking ER stress with astrocyte dysfunction. We have demonstrated that ER stress is directly associated with astrocyte dysfunction and induction of autophagy. Astrocyte ER stress can be down regulated by a chemical chaperon and up regulated by inducing Arg-61 apoE expression with an LXR agonist. In co-culture studies wild-type hippocampal neurons cultured on apoE3 and apoE4 knock-in primary astrocytes, apoE4 astrocytes induce deficits in hippocampal synaptic function, reducing presynaptic contacts on hippocampal neurons, reducing postsynaptic spine density, altering dendritic spine morphology, and reducing arc immediate early gene expression in response to BDNF. Interestingly, astrocyte Arg-61 apoE induces autophagy in neighboring neurons in vivo and in vitro. Combined these results suggest that astrocyte apoE4-induced hippocampal synaptic dysfunction and apoE4-induced astrocyte dysfunction represents early stage contributors to AD pathogenesis, in which astrocytes act in a non-cell-autonomous manner.

Insights into the Regulation of apoE & Aβ Levels in vivo 

Jungsu Kim, PhD, Washington University School of Medicine

Apolipoprotein E (ApoE) e4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). Previous studies suggest that the effect of ApoE on amyloid-β (Aβ) accumulation plays a major role in AD pathogenesis. Therefore, identification and functional characterization of proteins that control ApoE metabolism may provide new AD treatment strategy. For example, our recent study demonstrates that overexpression of low-density lipoprotein receptor protein in the brain dramatically inhibits amyloid plaque deposition. To determine whether human ApoE isoforms differentially affect Ab synthesis and/or clearance in the brain, we developed two novel methodologies, in vivo microdialysis and in vivo stable isotope pulse labeling mass spectrometry. I will present our recent Ab metabolism study data from human ApoE knock-in mouse models. In addition, we tested whether decreasing human ApoE levels will have a beneficial or deleterious effect on Aβ accumulation in vivo. We generated human ApoE isoform haploinsufficient mouse models by crossing APPPS1-21 mice with human ApoE isoform knock-in mice. Results from ApoE gene dosage study will be presented.

The Importance of Apolipoprotein E Function for the Beneficial Effects of LXR Agonists in the Damaged Central Nervous System

Cheryl L. Wellington, PhD, University of British Columbia, Vancouver

Apolipoprotein E (apoE) is the lipoprotein expressed in the central nervous system (CNS). ApoE is also the best validated genetic risk factor for Alzheimer's Disease (AD) and outcome following a wide a variety of acute neurological insults. The cholesterol transporter ABCA1 moves lipids onto apoE as the rate-limiting step in brain HDL biosynthesis. In AD mice, ABCA1 deficiency exacerbates amyloidogenesis, whereas selective overexpression of ABCA1 ameliorates amyloid burden. Liver X Receptor (LXR) agonists such as GW3965, which stimulate ABCA1 and apoE expression, reduce Aβ levels and rescue cognitive deficits in AD mice. We show that ABCA1-mediated lipidation of apoE is a crucial mechanism underlying the beneficial effects of LXR agonists on cognition and Aβ metabolism and highlights ABCA1 and apoE as a potential therapeutic targets for AD. We also show that the ability of GW3965 to promote motor and cognitive recovery after mild concussive brain injury is reduced in apoE-deficient mice. Together, these observations support a central role for apoE function in mediating the beneficial effects of LXR agonists for both chronic and acute CNS damage.

Modulating ApoE3 as a Novel Therapeutic Intervention for the Treatment of Alzheimer's Disease

David Riddell, PhD, Pfizer Research and Development

Recent evidence has suggested a potential role for APP in the regulation of brain Apolipoprotein E (ApoE) and cholesterol metabolism. In support of this function we have previously presented data from a transcriptional profiling study which demonstrates dysregulation of cholesterol-related genes in the Tg2576 APP transgenic mouse model of AD. We have now extended these findings to investigate the effects of APP transgene expression on ApoE metabolism. Surprisingly, although cholesterol biosynthesis machinery was activated in Tg2576 mice, total brain cholesterol levels were unchanged, while the levels of cholesterol intermediates were decreased. Given that cholesterol biosynthesis is generally activated when there is a reduced delivery of cholesterol to the cell, this gene signature suggests that there may be a deficient cholesterol delivery to these neurons. Indeed, despite the increased protein levels of the cholesterol transport molecule (apoE) and receptor (LDLR) in Tg2576 mouse brains, cholesterol endocytosis, measured by fluorescence-labelled LDL uptake, was found significantly (and specifically) impaired in Tg2576 hippocampal neurons. In a parallel set of studies, we and others have recently shown that apoE4 is linked to reduced apoE protein levels and a reduced capacity for astrocytes to deliver cholesterol to neurons. These data imply that processing of APP may serve a critical role in regulating neuronal cholesterol endocytosis and that APP and apoE mutations may converge on the same physiological pathway leading to reduced neuronal cholesterol delivery to neurons. Given that delivery of lipid to neurons has been hypothesized to be essential for synaptogenesis, these data suggest that promoting cholesterol endocytosis potentially via apoE upregulation may be a novel therapeutic intervention for the treatment of AD.

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