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Date: 18 Oct 2022 (Tuesday)
Time: 9 - 10am Format: Zoom Webinar (registration is required) Hosted by: Hongyan WANG, Duke-NUS Medical School |
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Speaker's information
Li-Huei TSANG Picower Institute for Learning and Memory at MIT, USA "Uncovering the role of Alzheimer’s disease risk genes using stem cells and human brains" |
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ABSTRACT
Alzheimer's disease (AD) is a debilitating brain disorder with staggering human and financial costs. While genomic studies increasingly identify genetic risk alleles that correlate with AD, there is still no clear picture of the underlying molecular and cellular mechanisms involved. My lab uses a multi-pronged approach to delineating how cellular, molecular and brain circuit dysfunctions contribute to AD. We recently reported the first single-nucleus transcriptomic analysis of the prefrontal cortex to accurately map the cell types and molecular pathways impacted by AD. Apolipoprotein E4 (ApoE4) is the strongest known genetic risk variant for sporadic Alzheimer’s disease (AD), but a comprehensive understanding of the cell-type-specific effects of APOE4 in the human brain in the presence and absence of AD pathology has yet to be achieved. Our recent analysis of single nucleus transcriptomics from a sex-balanced cohort of individuals comprised of APOE3 and E4 carriers indicated that cell-type-specific ApoE effects can arise in non-ApoE-expressing cell types. We also identified multiple processes that are perturbed in AD pathology exclusively in the context of ApoE4. In parallel, we conducted lipidomic analyses in ApoE4-iPSC-induced astrocytes derived from human ApoE4 carriers. These results revealed that ApoE4 causes widespread changes in lipid homeostasis that result in increased unsaturation of fatty acids and an accumulation of neutral lipids in lipid droplets in astrocytes. In addition, ApoE4 oligodendrocytes exhibit increased cholesterol pathway activity and decreased myelination gene expression. Taken together, our collected body of work illustrates how ApoE4 causes widespread molecular and cellular alterations in multiple cell types to facilitate the development of AD phenotypes.
BIO
Li-Huei Tsai is the Director of the Picower Institute for Learning and Memory and a Picower Professor of Neuroscience at the Massachusetts Institute of Technology,. She obtained her Ph.D. from the University of Texas Southwestern Medical Center in Dallas, TX and completed her postdoctoral training at Cold Spring Harbor Laboratories and Massachusetts General Hospital. Tsai became Assistant Professor of Pathology at Harvard Medical School and was promoted to tenured Professor at Harvard in 2002. She relocated to Massachusetts Institute of Technology in 2006. She was an Investigator of the Howard Hughes Medical Institute from 1997 to 2013. Tsai is also a Fellow of the American Association for the Advancement of Science, a Fellow of the National Academy of Inventors, a Member of the National Academy of Medicine, an Academician of the Academia Sinica in Taiwan, and a Member of the American Academy of Arts and Sciences. Tsai is interested in elucidating the pathogenic mechanisms underlying neurological disorders that impact learning and memory. She is a recipient of the Mika Salpeter Lifetime Achievement Award, and the 2018 Hans Wigzell Research Foundation Science Prize for her research on Alzheimer’s disease.
Alzheimer's disease (AD) is a debilitating brain disorder with staggering human and financial costs. While genomic studies increasingly identify genetic risk alleles that correlate with AD, there is still no clear picture of the underlying molecular and cellular mechanisms involved. My lab uses a multi-pronged approach to delineating how cellular, molecular and brain circuit dysfunctions contribute to AD. We recently reported the first single-nucleus transcriptomic analysis of the prefrontal cortex to accurately map the cell types and molecular pathways impacted by AD. Apolipoprotein E4 (ApoE4) is the strongest known genetic risk variant for sporadic Alzheimer’s disease (AD), but a comprehensive understanding of the cell-type-specific effects of APOE4 in the human brain in the presence and absence of AD pathology has yet to be achieved. Our recent analysis of single nucleus transcriptomics from a sex-balanced cohort of individuals comprised of APOE3 and E4 carriers indicated that cell-type-specific ApoE effects can arise in non-ApoE-expressing cell types. We also identified multiple processes that are perturbed in AD pathology exclusively in the context of ApoE4. In parallel, we conducted lipidomic analyses in ApoE4-iPSC-induced astrocytes derived from human ApoE4 carriers. These results revealed that ApoE4 causes widespread changes in lipid homeostasis that result in increased unsaturation of fatty acids and an accumulation of neutral lipids in lipid droplets in astrocytes. In addition, ApoE4 oligodendrocytes exhibit increased cholesterol pathway activity and decreased myelination gene expression. Taken together, our collected body of work illustrates how ApoE4 causes widespread molecular and cellular alterations in multiple cell types to facilitate the development of AD phenotypes.
BIO
Li-Huei Tsai is the Director of the Picower Institute for Learning and Memory and a Picower Professor of Neuroscience at the Massachusetts Institute of Technology,. She obtained her Ph.D. from the University of Texas Southwestern Medical Center in Dallas, TX and completed her postdoctoral training at Cold Spring Harbor Laboratories and Massachusetts General Hospital. Tsai became Assistant Professor of Pathology at Harvard Medical School and was promoted to tenured Professor at Harvard in 2002. She relocated to Massachusetts Institute of Technology in 2006. She was an Investigator of the Howard Hughes Medical Institute from 1997 to 2013. Tsai is also a Fellow of the American Association for the Advancement of Science, a Fellow of the National Academy of Inventors, a Member of the National Academy of Medicine, an Academician of the Academia Sinica in Taiwan, and a Member of the American Academy of Arts and Sciences. Tsai is interested in elucidating the pathogenic mechanisms underlying neurological disorders that impact learning and memory. She is a recipient of the Mika Salpeter Lifetime Achievement Award, and the 2018 Hans Wigzell Research Foundation Science Prize for her research on Alzheimer’s disease.