GSE113539
IL-1ß driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia
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-1ß 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-1ß-induced plaque clearance. To date, however, the mechanisms of IL-1ß-induced plaque clearance remain poorly understood. To determine whether IL-1ß-induced plaque clearance is due to enhanced microglial phagocytosis of Aß, APP/PS1 mice induced to express mature human IL-1ß in the hippocampus via adenoviral transduction were treated with the Aß fluorescent probe methoxy-X04 (MX04) and microglial internalization of Aß was analyzed by flow cytometry and immunohistochemistry. We found that resident microglia (CD45loCD11b+) constituted >70% of the MX04+ cells in both control and IL-1ß-treated conditions, and that <10% of MX04+ cells were recruited myeloid cells (CD45hiCD11b+). However, we found that IL-1ß treatment did not augment the percentage of MX04+ microglia nor the quantity of Aß internalized by individual microglia. Instead, we found that IL-1ß treatment resulted in a significant increase in the total number of MX04+ microglia in the hippocampus due to IL-1ß-induced proliferation. Consistent with these results, transcriptomic analyses revealed very similar gene expression profiles between MX04+ and MX04- microglia, indicating IL-1ß does not drive enhanced expression of phagocytosis-related genes. By contrast, IL-1ß treatment was associated with large-scale changes in the expression of genes related to proliferation, immune function and inflammation. Together, these studies demonstrate that IL-1ß induces microglial proliferation and the expression of genes involved in inflammatory immune functions that may be related to Aß clearance. Overall design: Hippocampal microglia mRNA profiles of 8-month-old APP/PS1-rAAV2-Phe and APP/PS1-rAAV2-IL-1ß further sorted on MX04+ (Aß+) and MX04- (Aß-). Two biological replicates of pooled cells from 6-8 APP/PS1 mouse hippocampi for each experimental group were sequenced using the Illumina HiSeq 2500.