INPP5D expression is associated with risk for Alzheimer’s disease and induced by plaque-associated microglia
Andy P Tsai,
Peter Bor-Chian Lin,
Brad T. Casali,
Bruce T. Lamb,
Gary E. Landreth,
Adrian L. Oblak,
Posted 31 Aug 2020
bioRxiv DOI: 10.1101/2020.08.31.276444
Posted 31 Aug 2020
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.
- Downloaded 565 times
- Download rankings, all-time:
- Site-wide: 75,968
- In neuroscience: 10,935
- Year to date:
- Site-wide: 85,777
- Since beginning of last month:
- Site-wide: 116,010
Downloads over time
Distribution of downloads per paper, site-wide
- 27 Nov 2020: The website and API now include results pulled from medRxiv as well as bioRxiv.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!