INPP5D expression is associated with risk for Alzheimer's disease and induced by plaque-associated microglia
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Abstract
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. We performed differential gene expression analysis to investigate INPP5D expression in AD 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. 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. 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.
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INPP5D expression increases with progression of clinical late-onset Alzheimer's disease and with aging in the 5XFAD mouse model.
“Additionally, INPP5D expression increases with progression of clinical LOAD and with aging in the 5XFAD mouse model.15”
From Microglial <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [15]
The Results section ('INPP5D expression levels are increased in AD') reports higher expression in LOAD patients than in controls in three brain regions, and higher expression than in MCI subjects in the inferior frontal gyrus. It does not establish that expression increases as clinical LOAD progresses within patients. The mouse-model Results section reports increased Inpp5d expression at multiple ages in 5xFAD mice compared with wild-type controls, supporting the aging-related part of the claim. (LLM, conf=0.83)
Experimental — accuracy not yet measuredUpregulated INPP5D levels in peripheral myeloid cells and the brain of LOAD patients indicate that INPP5D is involved in AD pathogenesis.
“Upregulated INPP5D levels in the peripheral myeloid cells and the brain of LOAD patients indicate that INPP5D is involved in AD pathogenesis.8,9”
From <i>INPP5D</i> deficiency attenuates amyloid pathology in a mouse model of Alzheimer's disease (2023) · cites this paper as [8]
The Results section reports increased INPP5D expression in several brain regions of patients with late-onset AD, and the Conclusions link INPP5D to AD pathophysiology. The paper does not report upregulated INPP5D in peripheral myeloid cells from those patients; its myeloid-cell findings concern brain microglia, including in mice. No page numbers are available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredOne study found elevated INPP5D mRNA expression in human AD brains that positively correlated with amyloid plaque density, and elevated Inpp5d mRNA and protein expression in 5xFAD mice throughout disease progression.
“One study found elevated INPP5D mRNA expression in human AD brains that positively correlated with amyloid plaque density, and elevated Inpp5d mRNA and protein expression in 5xFAD mice throughout disease progression [168].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [168]
The Results sections report increased INPP5D expression in several brain regions of patients with late-onset AD and a positive association with amyloid plaque density. In 5xFAD mice, mRNA was elevated at four, six, eight, and twelve months, but protein was assessed only at four and eight months, with p=0.06. Thus, the claim that both mRNA and protein were elevated throughout disease progression goes beyond the reported measurements. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSHIP1 protein expression was identified in plaque-associated microglia of 5xFAD mice, with phagocytic microglia showing a reduction of Inpp5d expression compared to non-phagocytic microglia.
“SHIP1 protein expression was identified in plaque-associated microglia of 5xFAD mice, with phagocytic microglia showing a reduction of Inpp5d expression compared to non-phagocytic microglia [168, 169].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [168]
The Results section reports INPP5D (SHIP1) protein in plaque-associated microglia of 5xFAD mice. It also reports lower Inpp5d expression in phagocytic than non-phagocytic microglia, but that comparison comes from transcriptomic data on wild-type mice injected with labeled apoptotic neurons, not from 5xFAD mice. No page numbers are provided in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredINPP5D plays a role in AD pathogenesis.
“INPP5D plays a role in AD pathogenesis, and remains a potential target for microglia-focused AD therapies,15”
From Microglial <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [15]
SHIP1 protein is elevated in the 5xFAD mouse.
“Although SHIP1 protein has been shown to be elevated in the 5xFAD mouse,15”
From Microglial <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [15]
RNA levels of INPP5D are elevated in Alzheimer's disease brain.
“confirm previous findings that RNA levels of INPP5D are elevated in AD brain21.”
From INPP5D regulates inflammasome activation in human microglia (2023) · cites this paper as [21]
Loss of Inpp5d alters amyloid pathology in models of amyloidosis.
“Loss of Inpp5d alters amyloid pathology in models of amyloidosis.”
From Loss of <i>Inpp5d</i> has disease‐relevant and sex‐specific effects on glial transcriptomes (2024) · cites this paper as [17]
The Results section reports increased Inpp5d expression in 5xFAD mice, not the effect of losing Inpp5d on amyloid pathology. The Discussion says findings from an Inpp5d-inactivated mouse model will help determine its role in disease progression; the Conclusions likewise place loss-of-function effects in future studies. Searches for loss of Inpp5d and amyloid pathology found no reported outcome. (LLM, conf=0.76)
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- Authors
- Tsai, A. P., Lin, P. B.-C., Dong, C., Moutinho, M., Casali, B. T., Liu, Y., Lamb, B. T., Landreth, G. E., Oblak, A. L., & Nho, K.
- Affiliations
- Indiana University School of Medicine (US)
- Corresponding author
- Oblak, Adrian L.
- Nho, Kwangsik
- ORCID
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2021-06
- Volume
- 153
- Pages
- 105303
- ISSN
- 0969-9961 (ISSN-L)
- PMC
- PMC8082515
- OpenAlex
- W3130754838
- Cited by
- 104
- References
- 10
- Citations by year
- 2026: 10 · 2025: 17 · 2024: 16 · 2023: 28 · 2022: 23 · 2021: 10
- FWCI
- 8.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Neurobiology of Disease (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- IUScholarWorks (Indiana University) (submittedVersion)
- Funders
- National Institute on Aging (K01 AG054753, R03 AG063250, U54 AG054345, RF1 AG050597, RF1 AG051495, K?N)
- National Institutes of Health (NLM R01 LM012535)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- INPP5D, SHIP1, Alzheimer's disease, late-onset Alzheimer's disease, amyloid plaques, plaque-associated microglia, microglial activation, microglia depletion, PLX5622, 5xFAD mice, neuroinflammation, gene expression, therapeutic target
- MeSH terms
- Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, RNA-Seq, Aged, Aged, 80 and over, Alzheimer Disease, Animals, Female, Humans, Male, Mice, Transgenic, RNA, Messenger, Microglia, Mice, Plaque, Amyloid
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