The National Heart, Lung, and Blood Institute (NHLBI) convened a working group (WG) on Lipid and Lipoprotein Metabolism and Alzheimer’s Disease (AD) and AD-Related Dementias in Bethesda, Maryland.
Genetic studies in Alzheimer’s disease (AD) strongly suggest that lipoprotein metabolism is one of the major pathways in the pathogenesis of AD. Currently, several gene variants or isoforms (e.g., apoE, apoJ, clusterin, ABCA7, SORL1, PICALM, and BIN1) that are related to lipid metabolism, transport, trafficking, and endocytosis have been associated with increased risk for AD. However, the underlying mechanism(s) and what exact roles lipids play in the development of AD are poorly understood.
The study of lipid metabolic pathways in the central nervous system (CNS) has been largely neglected to date. However, understanding how lipid/lipoprotein metabolism in the brain and body affect cognitive function is essential for establishing the mechanistic basis on which effective therapeutics and novel diagnostics for AD can be developed. Thus, coordinated efforts to combine expertise in neurobiology and lipid biology, which is readily available at different institutes at the NIH, are paramount to achieving the goals that have been set as a national priority for the prevention and effective treatment of AD and other neurodegenerative diseases.
Traditionally, investigators with the most experience in lipid and lipoprotein metabolism are funded by NHLBI, while investigators studying neurodegeneration are usually funded by the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS). Thus, very few NHLBI-funded investigators with strong expertise in lipid metabolism are able to cross the field to study lipid metabolism in CNS and examine the roles of lipids in the pathogenesis of AD and AD-related dementias, and vice versa. The goal of the working group was to bring together experts from both areas of lipid and lipoprotein metabolism and neurodegeneration to examine the current state of the science relating lipid and lipoprotein metabolism and AD, to identify gaps and barriers that would need to be removed to help move the field forward, and to recommend future research opportunities for NHLBI in lipid and lipoprotein metabolism and AD.
Presentations and discussions focused on the following themes:
- ApoE and ApoE receptors in the CNS and beyond, and their relations to neurodegenerative and vascular diseases
- Neuronal cell biology and lipid trafficking and transport
- Neurovascular mechanisms and neurodegeneration
- Neuronal lipid metabolism, lipid signaling, and inflammation
- Alzheimer’s disease-related dementia research in NHLBI cohort studies
Several under-researched areas were identified, including the role of the blood-brain barrier (BBB), neurovascular and neurosynaptic mechanisms, and lipid biology of the CNS in the pathogenesis of human dementia and AD.
Extensive expertise exists among NIH investigators in lipid and lipoprotein metabolism and AD and AD-related dementias at individual Institutes (e.g., NHLBI, NIA, and NINDS). Current funding and grant review structure hinder the cross pollination between the two fields. To accelerate progress toward the understanding and therapeutic intervention in AD and AD-related dementias, it is essential to integrate the wealth of scientific insights from all NIH institutes and combat the devastating diseases collaboratively across NIH.
The WG recommended to:
- Explore mechanisms by which NIH institutes could facilitate this cross-cutting research
- Engage in the NIH/NHLBI peer review process actively and partner with review staff to recommend qualified reviewers with sufficient expertise in neuroscience and lipid biology fields
- Encourage multidisciplinary and collaborative research approaches; for example, establish partnerships with scientists from other disciplines (e.g., physics, engineering, computational biology, structural biology) to apply new technologies and approaches to study lipoprotein and neurovasculature and AD
- Develop effective training programs to nurture the next generation of scientists and enable them to cross the barriers between the two fields
Future research opportunities:
- Study the lipid biology and pathophysiology of the brain
- Examine the role of lipoproteins and lipoprotein modifying/lipid transport enzymes and proteins in the interstitial space of the CNS
- Develop new tools or techniques that allow the interrogation of brain lipid metabolism within and in the space surrounding neurons and synapses
- Devise methods required for the quantitative evaluation of metabolic disturbances in the CNS by combining the expertise from traditional lipid biochemists and neurophysiologists
- Investigate the neurovasculature and the BBB in an analogous interdisciplinary manner
- Explore the mechanisms by which large and small molecules with therapeutic potential cross the BBB and discover the most effective therapeutics to treat AD and AD related dementia
- Develop a comprehensive proteomics and RNAseq molecular atlas of the BBB in animals and humans. This would represent a valuable resource for drug screening, design of novel drugs easily accessible to CNS through the BBB and new transgenic models for neurovascular and neurological syndromes
- Develop a molecular classification of cerebral small vessel disease, perform advanced lipoprotein testing and explore their relationship with dementia, determine the association of lipid disorders with dementia, and investigate the role of post-prandial lipids in dementia
- Examine whether lipid metabolic factors broadly influence susceptibility to neurodegenerative disease and explore how lipid-lowering medications as well as BBB modifying drugs affect neurodegenerative syndromes
- Improve accessibility of animal models: some of the essential mouse models in the field, most notably the human ApoE targeted replacement mice, are effectively inaccessible to the vast majority of scientists, due to proprietary arrangements with commercial entities
- Leverage existing resources such as NHLBI cohorts and diverse mouse strains (e.g. the Hybrid Mouse Diversity Panel (HMDP) at UCLA) to study AD and related dementia
The working group plans to prepare a manuscript for publication in a peer-reviewed and open access journal.
Lijuan Liu, Ph.D.
Michelle Olive, Ph.D.
Working Group Participants:
Chair: Joachim Herz, M.D., UT Southwestern Medical Center
- Shawn Ferguson, Ph.D., Yale University
- Christopher Glass, M.D., Ph.D., University of California, San Diego
- David Holtzman, M.D., Washington University
- Costantino Iadecola, M.D., Cornell University
- Alan Remaley, M.D., Ph.D., NHLBI
- Tarek Samad, Ph.D., Pfizer Worldwide Research and Development
- Peter Tontonoz, M.D., Ph.D., University of California, Los Angeles
- Cheryl Wellington, Ph.D., The University of British Columbia
- Jacqueline Wright, Dr.P.H., NHLBI
- Berislav Zlokovic, M.D., Ph.D., University of Southern California
Participants from NHLBI and other NIH Institutes:
- Yves Rosenberg, M.D., NHLBI
- Zorina Galis, Ph.D., NHLBI
- Suzana Petanceska, Ph.D., NIA
- Luke Stoeckel, Ph.D. NIDDK
- Francesca Bosetti, Pharm.D., Ph.D., NINDS
- Michael Ward, M.D., Ph.D., NINDS