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The microglial transcriptome of a novel murine model of Alzheimer's Disease: phagocytically active and inactive microglia from homozygous App-SAA mice and WT littermate controls.

ABSTRACT: We created a novel murine model of Alzheimer's Disease using a knock-in strategy to humanize the sequence of the murine App gene and introduced three familial AD (FAD) mutations, Swedish (Swedish (KM670/671NL), Arctic (E693G)) and Austrian (T712I). To determine whether App-SAA microglia exhibit cellular dysfunctions and whether these dysfunctions relate to fibrillar Ab internalization, mice were intraperitoneally (i.p.) injected with 10 mg/kg methoxy-X04. 24 hours after injection, mice were perfused with PBS, cortical and hippocampal tissues were dissected and processed into single-cell suspension and methoxy-X04-negative and methoxy-X04-positive microglia were isolated using FACS. Mirroring our gene expression studies, we found profound alterations of the AppSAA microglia transcriptome; these changes were exacerbated in methoxy-X04 positive compared to negative cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE158153 | GEO | 2021/01/20

REPOSITORIES: GEO

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Project description: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-1β 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-1β-induced plaque clearance. To date, however, the mechanisms of IL-1β-induced plaque clearance remain poorly understood. To determine whether IL-1β-induced plaque clearance is due to enhanced microglial phagocytosis of Aβ, APP/PS1 mice induced to express mature human IL-1β in the hippocampus via adenoviral transduction were treated with the Aβ fluorescent probe methoxy-X04 (MX04) and microglial internalization of Aβ was analyzed by flow cytometry and immunohistochemistry. We found that resident microglia (CD45loCD11b+) constituted >70% of the MX04+ cells in both control and IL-1β-treated conditions, and that <10% of MX04+ cells were recruited myeloid cells (CD45hiCD11b+). However, we found that IL-1β treatment did not augment the percentage of MX04+ microglia nor the quantity of Aβ internalized by individual microglia. Instead, we found that IL-1β treatment resulted in a significant increase in the total number of MX04+ microglia in the hippocampus due to IL-1β-induced proliferation. Consistent with these results, transcriptomic analyses revealed very similar gene expression profiles between MX04+ and MX04- microglia, indicating IL-1β does not drive enhanced expression of phagocytosis-related genes. By contrast, IL-1β 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-1β induces microglial proliferation and the expression of genes involved in inflammatory immune functions that may be related to Aβ clearance.

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The microglial transcriptome of a novel murine model of Alzheimer's Disease: phagocytically active and inactive microglia from homozygous App-SAA mice and WT littermate controls.

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