IL-1?-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia.
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ABSTRACT: BACKGROUND:Neuroinflammation is thought to contribute to the pathogenesis of Alzheimer's disease (AD), yet numerous studies have demonstrated a beneficial role for neuroinflammation in amyloid plaque clearance. We have previously shown that sustained expression of IL-1? in the hippocampus of APP/PS1 mice decreases amyloid plaque burden independent of recruited CCR2+ myeloid cells, suggesting resident microglia as the main phagocytic effectors of IL-1?-induced plaque clearance. To date, however, the mechanisms of IL-1?-induced plaque clearance remain poorly understood. METHODS:To determine whether microglia are involved in IL-1?-induced plaque clearance, APP/PS1 mice induced to express mature human IL-1? in the hippocampus via adenoviral transduction were treated with the A? fluorescent probe methoxy-X04 (MX04) and microglial internalization of fibrillar A? (fA?) was analyzed by flow cytometry and immunohistochemistry. To assess microglial proliferation, APP/PS1 mice transduced with IL-1? or control were injected intraperitoneally with BrdU and hippocampal tissue was analyzed by flow cytometry. RNAseq analysis was conducted on microglia FACS sorted from the hippocampus of control or IL-1?-treated APP/PS1 mice. These microglia were also sorted based on MX04 labeling (MX04+ and MX04- microglia). RESULTS:Resident microglia (CD45loCD11b+) constituted > 70% of the MX04+ cells in both Phe- and IL-1?-treated conditions, and < 15% of MX04+ cells were recruited myeloid cells (CD45hiCD11b+). However, IL-1? treatment did not augment the percentage of MX04+ microglia nor the quantity of fA? internalized by individual microglia. Instead, IL-1? increased the total number of MX04+ microglia in the hippocampus due to IL-1?-induced proliferation. In addition, transcriptomic analyses revealed that IL-1? treatment was associated with large-scale changes in the expression of genes related to immune responses, proliferation, and cytokine signaling. CONCLUSIONS:These studies show that IL-1? overexpression early in amyloid pathogenesis induces a change in the microglial gene expression profile and an expansion of microglial cells that facilitates A? plaque clearance.
SUBMITTER: Rivera-Escalera F
PROVIDER: S-EPMC6902486 | biostudies-literature | 2019 Dec
REPOSITORIES: biostudies-literature
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