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Published on: February 5, 2018
Cholesterol and matrisome pathways dysregulated in astrocytes and microglia
Julia Tcw1, Lu Qian1, Nina H Pipalia2
1Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Nash Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
The strongest Alzheimer's risk factor, apolipoprotein E ε4 (APOE4), disrupts brain cell lipid metabolism. This APOE4-driven dysregulation in astrocytes and microglia contributes to Alzheimer's disease risk.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Apolipoprotein E ε4 (APOE4) is the primary genetic risk factor for Alzheimer's disease (AD).
- The precise cellular mechanisms by which APOE4 influences brain function and AD pathogenesis are not fully understood.
Purpose of the Study:
- To investigate the impact of APOE4 on human brain cell types.
- To elucidate the cellular and molecular pathways affected by APOE4 in the context of AD risk.
Main Methods:
- Utilized population and isogenic human induced pluripotent stem cells (iPSCs).
- Analyzed post-mortem human brain tissue.
- Employed APOE targeted replacement mouse models.
- Conducted global transcriptomic analyses.
Main Results:
- APOE4 local haplotype, not a single allele, correlates with AD risk.
- Identified human-specific, APOE4-driven lipid metabolic dysregulation in astrocytes and microglia.
- Observed enhanced de novo cholesterol synthesis and lysosomal cholesterol sequestration in APOE4 astrocytes.
- Found matrisome dysregulation linked to glial activation and lipid biosynthesis in astrocytes co-cultured with neurons.
Conclusions:
- APOE4 initiates glia-specific cellular dysregulation.
- APOE4 causes non-cell autonomous effects contributing to AD risk.
- Lipid metabolism and matrisome alterations in astrocytes and microglia are key pathways affected by APOE4.
