期刊
MOLECULAR PSYCHIATRY
卷 26, 期 10, 页码 5620-5635出版社
SPRINGERNATURE
DOI: 10.1038/s41380-020-0856-8
关键词
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资金
- Fisher Center for Alzheimer's Research Foundation
- JPB Foundation
- Cure Alzheimer's Fund
- Pew Charitable Trusts
- US National Institutes of Health (NIH) [R01 GM071966]
- Empire State Stem Cell Fund through NYSDOH [C023046]
Microglia containing phospho-deficient mutant PS1 show a slower kinetic response to brain micro injury in vivo and an inability to degrade A beta oligomers, leading to severe A beta accumulation in microglia in an Alzheimer's mouse model. This demonstrates a novel mechanism by which PS1 modulates microglial function and contributes to Alzheimer's-associated phenotypes.
Amyloid-beta peptide (A beta) accumulation in the brain is a hallmark of Alzheimer's Disease. An important mechanism of A beta clearance in the brain is uptake and degradation by microglia. Presenilin 1 (PS1) is the catalytic subunit of gamma-secretase, an enzyme complex responsible for the maturation of multiple substrates, such as A beta. Although PS1 has been extensively studied in neurons, the role of PS1 in microglia is incompletely understood. Here we report that microglia containing phospho-deficient mutant PS1 display a slower kinetic response to micro injury in the brain in vivo and the inability to degrade A beta oligomers due to a phagolysosome dysfunction. An Alzheimer's mouse model containing phospho-deficient PS1 show severe A beta accumulation in microglia as well as the postsynaptic protein PSD95. Our results demonstrate a novel mechanism by which PS1 modulates microglial function and contributes to Alzheimer's -associated phenotypes.
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