Cell-autonomous effects of APOE4 in restricting microglial response in brain homeostasis and Alzheimer's disease.

Autor: Liu CC; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. liu.chiachenjen@gmail.com.; Neurodegenerative Diseases Research Unit, Biogen, Cambridge, MA, USA. liu.chiachenjen@gmail.com., Wang N; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.; Department of Neurology, Mayo Clinic, Rochester, MN, USA., Chen Y; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Inoue Y; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Shue F; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Ren Y; Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA., Wang M; Department of Genetics and Genomic Sciences, Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Qiao W; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Ikezu TC; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Li Z; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Zhao J; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Martens Y; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Doss SV; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Rosenberg CL; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Jeevaratnam S; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Jia L; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Raulin AC; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Qi F; Department of Neurology, Mayo Clinic, Rochester, MN, USA., Zhu Y; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Alnobani A; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Knight J; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Chen Y; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Linares C; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Kurti A; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Fryer JD; Department of Neuroscience, Mayo Clinic, Scottsdale, AZ, USA., Zhang B; Department of Genetics and Genomic Sciences, Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Wu LJ; Department of Neurology, Mayo Clinic, Rochester, MN, USA., Kim BYS; Department of Neurosurgery, The Brain Tumor Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Bu G; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. gbu@ust.hk.; Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China. gbu@ust.hk.
Jazyk: angličtina
Zdroj: Nature immunology [Nat Immunol] 2023 Nov; Vol. 24 (11), pp. 1854-1866. Date of Electronic Publication: 2023 Oct 19.
DOI: 10.1038/s41590-023-01640-9
Abstrakt: Microglial involvement in Alzheimer's disease (AD) pathology has emerged as a risk-determining pathogenic event. While apolipoprotein E (APOE) is known to modify AD risk, it remains unclear how microglial apoE impacts brain cognition and AD pathology. Here, using conditional mouse models expressing apoE isoforms in microglia and central nervous system-associated macrophages (CAMs), we demonstrate a cell-autonomous effect of apoE3-mediated microglial activation and function, which are negated by apoE4. Expression of apoE3 in microglia/CAMs improves cognitive function, increases microglia surrounding amyloid plaque and reduces amyloid pathology and associated toxicity, whereas apoE4 expression either compromises or has no effects on these outcomes by impairing lipid metabolism. Single-cell transcriptomic profiling reveals increased antigen presentation and interferon pathways upon apoE3 expression. In contrast, apoE4 expression downregulates complement and lysosomal pathways, and promotes stress-related responses. Moreover, in the presence of mouse endogenous apoE, microglial apoE4 exacerbates amyloid pathology. Finally, we observed a reduction in Lgals3-positive responsive microglia surrounding amyloid plaque and an increased accumulation of lipid droplets in APOE4 human brains and induced pluripotent stem cell-derived microglia. Our findings establish critical isoform-dependent effects of microglia/CAM-expressed apoE in brain function and the development of amyloid pathology, providing new insight into how apoE4 vastly increases AD risk.
(© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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