| First Author | Rivera-Escalera F | Year | 2019 |
| Journal | J Neuroinflammation | Volume | 16 |
| Issue | 1 | Pages | 261 |
| PubMed ID | 31822279 | Mgi Jnum | J:284868 |
| Mgi Id | MGI:6391588 | Doi | 10.1186/s12974-019-1645-7 |
| Citation | Rivera-Escalera F, et al. (2019) IL-1beta-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia. J Neuroinflammation 16(1):261 |
| abstractText | 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-1beta 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-1beta-induced plaque clearance. To date, however, the mechanisms of IL-1beta-induced plaque clearance remain poorly understood. METHODS: To determine whether microglia are involved in IL-1beta-induced plaque clearance, APP/PS1 mice induced to express mature human IL-1beta in the hippocampus via adenoviral transduction were treated with the Abeta fluorescent probe methoxy-X04 (MX04) and microglial internalization of fibrillar Abeta (fAbeta) was analyzed by flow cytometry and immunohistochemistry. To assess microglial proliferation, APP/PS1 mice transduced with IL-1beta 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-1beta-treated APP/PS1 mice. These microglia were also sorted based on MX04 labeling (MX04(+) and MX04(-) microglia). RESULTS: Resident microglia (CD45(lo)CD11b(+)) constituted > 70% of the MX04(+) cells in both Phe- and IL-1beta-treated conditions, and < 15% of MX04(+) cells were recruited myeloid cells (CD45(hi)CD11b(+)). However, IL-1beta treatment did not augment the percentage of MX04(+) microglia nor the quantity of fAbeta internalized by individual microglia. Instead, IL-1beta increased the total number of MX04(+) microglia in the hippocampus due to IL-1beta-induced proliferation. In addition, transcriptomic analyses revealed that IL-1beta 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-1beta overexpression early in amyloid pathogenesis induces a change in the microglial gene expression profile and an expansion of microglial cells that facilitates Abeta plaque clearance. |
