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INPP5D modulates TREM2 loss-of-function phenotypes in a β-amyloidosis mouse model

ABSTRACT: We crossed Tyrobp-deficient and Inpp5d-deficient mice with App(NL-G-F/NL-G-F) Alzheimer model mice (hereafter, NLGF) and generate Tyrobp-/-;Inpp5d+/-;NLGF mice to assess the role of Inpp5d in Tyrobp-/- mice. We isolated microglia from NLGF, Tyrobp-/-;NLGF, and Tyrobp-/-;Inpp5d+/-;NLGF mice and analyzed microglial transcriptome using RNA-sequencing. Tyrobp-/- microglia showed substantially different transcriptome compared with NLGF microglia. Previously described "disease asscociated microglia" genes were enriched in the differentially expressed genes in Tyrobp-/- microglia. On the other hand, Tyrobp-/-;Inpp5d+/-;NLGF microglia showed similar transcriptome to Tyrobp-/- microglia except several genes (e.g., Wdfy1, Mamdc2, Klrb1f). These data suggest Inpp5d modulates microglial functions without affecting disease associated microglial gene expression in Tyrobp-/-;NLGF micrglia.

ORGANISM(S): Mus musculus

PROVIDER: GSE172499 | GEO | 2023/02/24

REPOSITORIES: GEO

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Project description:Microglia and neuroinflammation are implicated in the development and progression of Alzheimer’s disease (AD). To better understand microglia-mediated processes in AD, we studied the function of INPP5D/SHIP1, a gene linked to AD through GWAS. Immunostaining and single nucleus RNA sequencing confirmed that INPP5D expression in the adult human brain is enriched in microglia. Examination of prefrontal cortex across a large cohort revealed reduced full-length soluble INPP5D protein levels in AD patient brains compared to cognitively normal controls. However, elevated INPP5D immunostaining in microglia in the AD brain was observed, which was driven by elevations in plaque-associated microglia suggesting that these two methods quantify different pools of INPP5D. Examination of INPP5D overexpression and bi-allelic loss-of-function in induced pluripotent stem cell derived microglia (iMGs) revealed that INPP5D LOF most closely resemble microglia in the AD brain with respect to immune signaling alterations, supporting the hypothesis that INPP5D function is reduced in AD microglia. The functional consequences of reduced INPP5D activity were evaluated in human iMGs, using both pharmacological inhibition of the phosphatase activity of INPP5D and genetic reduction in copy number. Unbiased transcriptional and proteomic profiling of these iMGs suggested an upregulation of innate immune signaling pathways, lower levels of scavenger receptors, reduced lysosomal proteins and altered inflammasome signaling with INPP5D reduction. INPP5D inhibition induced the secretion of IL-1ß and IL-18, further implicating inflammasome activation. Inflammasome activation was confirmed through visualization of inflammasome formation through ASC immunostaining in INPP5D-inhibited iMGs, increased cleaved caspase-1 and through rescue of elevated IL-1ß and IL-18 with caspase-1 and NLRP3 inhibitors. In accord, lower INPP5D is associated with higher IL-18 levels and an elevation in microglia with ASC specks in the AD brain. This work implicates INPP5D as a regulator of inflammasome signaling in human microglia.

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INPP5D modulates TREM2 loss-of-function phenotypes in a β-amyloidosis mouse model

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