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SUMMARY:Uncovering the role of Alzheimer’s disease risk genes using stem
  cells and human brains - Prof Li-Huei Tsai\, Massachusetts Institute of T
 echnology
DTSTART:20220119T160000Z
DTEND:20220119T170000Z
UID:TALK168068@talks.cam.ac.uk
CONTACT:105064
DESCRIPTION: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 c
 lear picture of the underlying molecular and cellular mechanisms involved.
  My lab uses a multi-pronged approach to delineating how cellular\, molecu
 lar 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. Ap
 olipoprotein E4 (ApoE4) is the strongest known genetic risk variant for sp
 oradic Alzheimer’s disease (AD)\, but a comprehensive understanding of t
 he 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 mu
 ltiple processes that are perturbed in AD pathology exclusively in the con
 text of ApoE4.  In parallel\, we conducted lipidomic analyses in ApoE4-iPS
 C-induced astrocytes derived from human ApoE4 carriers. These results reve
 aled that ApoE4 causes widespread changes in lipid homeostasis that result
  in increased unsaturation of fatty acids and an accumulation of neutral l
 ipids in lipid droplets in astrocytes. In addition\, ApoE4 oligodendrocyte
 s 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 multipl
 e cell types to facilitate the development of AD phenotypes.
LOCATION:https://zoom.us/j/99301642413
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