The Alzheimer's disease risk factor INPP5D restricts neuroprotective microglial responses in amyloid beta‐mediated pathology
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Introduction: Mutations in INPP5D, which encodes for the SH2‐domain‐containing inositol phosphatase SHIP‐1, have recently been linked to an increased risk of developing late‐onset Alzheimer's disease. While INPP5D expression is almost exclusively restricted to microglia in the brain, little is known regarding how SHIP‐1 affects neurobiology or neurodegenerative disease pathogenesis. Methods: We generated and investigated 5xFAD Inpp5dfl/flCx3cr1Ert2Cre mice to ascertain the function of microglial SHIP‐1 signaling in response to amyloid beta (Aβ)‐mediated pathology. Results: SHIP‐1 deletion in microglia led to substantially enhanced recruitment of microglia to Aβ plaques, altered microglial gene expression, and marked improvements in neuronal health. Further, SHIP‐1 loss enhanced microglial plaque containment and Aβ engulfment when compared to microglia from Cre‐negative 5xFAD Inpp5dfl/fl littermate controls. Discussion: These results define SHIP‐1 as a pivotal regulator of microglial responses during Aβ‐driven neurological disease and suggest that targeting SHIP‐1 may offer a promising strategy to treat Alzheimer's disease. Highlights: Inpp5d deficiency in microglia increases plaque‐associated microglia numbers. Loss of Inpp5d induces activation and phagocytosis transcriptional pathways. Plaque encapsulation and engulfment by microglia are enhanced with Inpp5d deletion. Genetic ablation of Inpp5d protects against plaque‐induced neuronal dystrophy.
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Previous studies in mouse models and immortalized microglia cell lines suggested a role for SHIP1 in regulating Aβ phagocytosis.
“Previous studies in mouse models and immortalized microglia cell lines suggested a role for SHIP1 in regulating Aβ phagocytosis60–62.”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [60]
Samuels et al. found that amyloid levels were not changed but microglial number and engagement with plaques increased.
“Amyloid levels were not changed but microglial number and engagement with plaques increased.”
From Loss of <i>Inpp5d</i> has disease‐relevant and sex‐specific effects on glial transcriptomes (2024) · cites this paper as [49]
Iguchi et al. provides evidence that Inpp5d loss increases glial engagement with plaques, as also observed by both Lin et al. and Samuels et al.
“Iguchi et al. provides evidence that Inpp5d loss increases glial engagement with plaques, as also observed by both Lin et al. and Samuels et al.”
From Loss of <i>Inpp5d</i> has disease‐relevant and sex‐specific effects on glial transcriptomes (2024) · cites this paper as [49]
Conditional knockout of Inpp5d in 3-week-old 5xFAD mice enhanced microglia recruitment to plaques, decreased microglial ramification, and ameliorated neuritic dystrophy but had no impact on plaque burden.
“In another recent study, conditional knock out of Inpp5d in 3-week-old 5xFAD mice similarly enhanced microglia recruitment to plaques, decreased microglial ramification, and ameliorated neuritic dystrophy but had no impact on plaque burden [173].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [173]
Recent studies showed that microglial deletion of Inpp5d protects against plaque-induced neuronal dystrophy in transgenic AD mice.
“Similarly, recent studies showed that microglial deletion of Inpp5d protects against plaque-induced neuronal dystrophy in transgenic AD mice 41,42 .”
From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as [41]
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Self-citation
- Authors
- Samuels, J. D., Moore, K. A., Ennerfelt, H. E., Johnson, A. M., Walsh, A. E., Price, R. J., & Lukens, J. R.
- Affiliations
- University of Virginia (US)
- Corresponding author
- Lukens, John R.
- ORCID
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2023-04-15
- Volume
- 19
- Issue
- 11
- Pages
- 4908-4921
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC10576836
- OpenAlex
- W4365815492
- Cited by
- 46
- References
- 16
- Citations by year
- 2026: 15 · 2025: 14 · 2024: 9 · 2023: 8
- FWCI
- 4.74
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Alzheimer s & Dementia (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Alzheimer's Association (ADSF-21-816651)
- Cure Alzheimer's Fund
- Owens Family Foundation
- National Institutes of Health (NIH T32)
- National Institute on Aging (RF1AG071996)
- National Institute of General Medical Sciences (T32GM008715)
- National Institute of Neurological Disorders and Stroke (R01NS106383, R01NS111102, T32NS115657)
- National Institute of Biomedical Imaging and Bioengineering (R01EB030744)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- INPP5D, SHIP1
- MeSH terms
- Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Alzheimer Disease, Animals, Disease Models, Animal, Mice, Transgenic, Risk Factors, Amyloid beta-Peptides, Microglia, Neurodegenerative Diseases, Mice, Plaque, Amyloid
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