IL-1[beta]-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia

• Published in: Journal of neuroinflammation 2019-12, Vol.16 (1)
• Main Authors: Rivera-Escalera, Fátima, Pinney, Jonathan J, Owlett, Laura, Ahmed, Hoda, Thakar, Juilee, Olschowka, John A, Elliott, Michael R, O'Banion, M. Kerry
• Format: Article
• Language: English
• Subjects: Advertising executives; Alzheimer's disease; Analysis; Brain; Gene expression; Genes; Genetic research; Immune response; Immunohistochemistry; Interleukins; Medical equipment industry; RNA sequencing; Transcription (Genetics)
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-019-1645-7

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[beta] in the hippocampus of APP/PS1 mice decreases amyloid plaque burden independent of recruited CCR2.sup.+ myeloid cells, suggesting resident microglia as the main phagocytic effectors of IL-1[beta]-induced plaque clearance. To date, however, the mechanisms of IL-1[beta]-induced plaque clearance remain poorly understood. Methods To determine whether microglia are involved in IL-1[beta]-induced plaque clearance, APP/PS1 mice induced to express mature human IL-1[beta] in the hippocampus via adenoviral transduction were treated with the A[beta] fluorescent probe methoxy-X04 (MX04) and microglial internalization of fibrillar A[beta] (fA[beta]) was analyzed by flow cytometry and immunohistochemistry. To assess microglial proliferation, APP/PS1 mice transduced with IL-1[beta] 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[beta]-treated APP/PS1 mice. These microglia were also sorted based on MX04 labeling (MX04.sup.+ and MX04.sup.- microglia). Results Resident microglia (CD45.sup.loCD11b.sup.+) constituted > 70% of the MX04.sup.+ cells in both Phe- and IL-1[beta]-treated conditions, and < 15% of MX04.sup.+ cells were recruited myeloid cells (CD45.sup.hiCD11b.sup.+). However, IL-1[beta] treatment did not augment the percentage of MX04.sup.+ microglia nor the quantity of fA[beta] internalized by individual microglia. Instead, IL-1[beta] increased the total number of MX04.sup.+ microglia in the hippocampus due to IL-1[beta]-induced proliferation. In addition, transcriptomic analyses revealed that IL-1[beta] 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[beta] overexpression early in amyloid pathogenesis induces a change in the microglial gene expression profile and an expansion of microglial cells that facilitates A[beta] plaque clearance. Keywords: Alzheimer's disease, Interleukin-1[beta], Neuroinflammation, Microglia, Phagocytosis, Amyloid plaque, Proliferation, MX04