INPP5D regulates inflammasome activation in human microglia

Abstract

Microglia and neuroinflammation play an important role in the development and progression of Alzheimer’s disease (AD). Inositol polyphosphate-5-phosphatase D (INPP5D/SHIP1) is a myeloid-expressed gene genetically-associated with AD. Through unbiased analyses of RNA and protein profiles in INPP5D-disrupted iPSC-derived human microglia, we find that reduction in INPP5D activity is associated with molecular profiles consistent with disrupted autophagy and inflammasome activation. These findings are validated through targeted pharmacological experiments which demonstrate that reduced INPP5D activity induces the formation of the NLRP3 inflammasome, cleavage of CASP1, and secretion of IL-1β and IL-18. Further, in-depth analyses of human brain tissue across hundreds of individuals using a multi-analytic approach provides evidence that a reduction in function of INPP5D in microglia results in inflammasome activation in AD. These findings provide insights into the molecular mechanisms underlying microglia-mediated processes in AD and highlight the inflammasome as a potential therapeutic target for modulating INPP5D-mediated vulnerability to AD.

Alteration of gene expression and protein solubility of the PI 5-phosphatase SHIP2 are correlated with Alzheimer’s disease pathology progression

“…SHIP1 (encoded by INPP5D ) is a paralog of SHIP2 and one of the most significant GWAS hits for LOAD [ 6 , 13 , 52 ]. SHIP1 and SHIP2 are differentially expressed: while our double immunofluorescence staining suggested SHIP2 is highly detected in astrocytes (also described in [ 65 ]), SHIP1 is predominantly expressed in microglia [ 22 , 84 ]. It has been recently shown that SHIP1 is depleted in the most soluble fraction of post-mortem AD brain lysates and that SHIP1 immunolabelling is upregulated in AD brain tissues, notably in plaque-associated microglia [ 22 ].…”

“…SHIP1 and SHIP2 are differentially expressed: while our double immunofluorescence staining suggested SHIP2 is highly detected in astrocytes (also described in [ 65 ]), SHIP1 is predominantly expressed in microglia [ 22 , 84 ]. It has been recently shown that SHIP1 is depleted in the most soluble fraction of post-mortem AD brain lysates and that SHIP1 immunolabelling is upregulated in AD brain tissues, notably in plaque-associated microglia [ 22 ]. Changes in the subcellular localization of SHIP1 and/or SHIP2 may have two consequences: it could affect its phosphatase activity being no more in contact with PI containing membranes, but it could also affect its adaptor function as a docking protein interacting with a cluster of distinct protein interactome in AD [ 60 ].…”

Microglial Senescence and Activation in Healthy Aging and Alzheimer’s Disease: Systematic Review and Neuropathological Scoring

“…Other recent evidence highlights the importance of IL-1α and TNF-α to stimulate microglial proliferation and promote primed phenotypes, while IL-1β is more related to a senescent/SASP microglial phenotype [57,58,184]. Moreover, a singular association between IL-33 expression and senescent microglial phenotypes has been recently observed [185], as well as a decrease in the inositol polyphosphate-5-phosphatase D (INPP5D) in microglia from human brain tissue favors the firing of the "inflammasome" in AD [186].…”

Development of a high-throughput, quantitative platform using human cerebral organoids to study virus-induced neuroinflammation in Alzheimer’s disease

“…There is mounting evidence that chronic neuroinflammation mediated by microglia and astrocytes can lead to Alzheimer's disease (AD) pathogenesis, disease progression and severity 1,2 . This evidence has led to active research on nonsteroidal anti-inflammatory drugs and modulation of key neuroinflammation targets for AD therapeutics, such as NLRP3 inflammasome, TREM2 and INPP5D [3][4][5][6][7] . It was also proposed that there is an infectious etiology in AD and viruses such as the double-stranded DNA herpes simplex virus (HSV-1) and single-stranded RNA influenza A virus (IAV) can trigger neuroinflammation that may lead to AD pathogenesis, progression or severity [8][9][10][11][12][13] .…”