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INPP5D expression is associated with risk for Alzheimer’s disease and induced by plaque-associated microglia

By Andy P. Tsai, Peter Bor-Chian Lin, Chuanpeng Dong, Miguel Moutinho, Brad T. Casali, Yunlong Liu, Bruce T. Lamb, Gary E. Landreth, Adrian L. Oblak, Kwangsik Nho

Posted 31 Aug 2020
bioRxiv DOI: 10.1101/2020.08.31.276444

Background Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, robust microgliosis, neuroinflammation, and neuronal loss. Genome-wide association studies recently highlighted a prominent role for microglia in late-onset AD (LOAD). Specifically, inositol polyphosphate-5-phosphatase ( INPP5D ), also known as SHIP1, is selectively expressed in brain microglia and has been reported to be associated with LOAD. Although INPP5D is likely a crucial player in AD pathophysiology, its role in disease onset and progression remains unclear. Methods We performed differential gene expression analysis to investigate INPP5D expression in LOAD and its association with plaque density and microglial markers using transcriptomic (RNA-Seq) data from the Accelerating Medicines Partnership for Alzheimer’s Disease (AMP-AD) cohort. We also performed quantitative real-time PCR, immunoblotting, and immunofluorescence assays to assess INPP5D expression in the 5xFAD amyloid mouse model. Results Differential gene expression analysis found that INPP5D expression was upregulated in LOAD and positively correlated with amyloid plaque density. In addition, in 5xFAD mice, Inpp5d expression increased as the disease progressed, and selectively in plaque-associated microglia. Increased Inpp5d expression levels in 5xFAD mice were abolished entirely by depleting microglia with the colony-stimulating factor receptor-1 antagonist PLX5622. Conclusions Our findings show that INPP5D expression increases as AD progresses, predominantly in plaque-associated microglia. Importantly, we provide the first evidence that increased INPP5D expression might be a risk factor in AD, highlighting INPP5D as a potential therapeutic target. Moreover, we have shown that the 5xFAD mouse model is appropriate for studying INPP5D in AD. ### Competing Interest Statement The authors have declared no competing interest. * AD : Alzheimer’s disease LOAD : late-onset AD GWAS : genome-wide association studies INPP5D : phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1 PI(3,4,5)P3 : phosphatidylinositol (3,4,5)-trisphosphate PI(3,4)P2 : phosphatidylinositol (3,4)-bisphosphate CSF : cerebrospinal fluid OR : odds ratio CI : confidence interval β : β coefficient WT : wild-type MCI : mild cognitive impairment APOE ε4 : apolipoprotein ε4 allele PFA : paraformaldehyde PCR : polymerase chain reaction Seq : sequencing ANOVA : analysis of variance qPCR : quantitative real-time PCR mAb : monoclonal antibody.

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