The Alzheimer's disease risk factor INPP5D restricts neuroprotective microglial responses in amyloid beta-mediated pathology

Alzheimers Dement. 2023 Nov;19(11):4908-4921. doi: 10.1002/alz.13089. Epub 2023 Apr 15.


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/fl Cx3cr1Ert2Cre 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.

Keywords: Alzheimer's disease; INPP5D; SHIP-1; amyloid beta; amyloidosis; disease-associated microglia; microglia; neurodegenerative disease; neuroimmunology.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease* / pathology
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Disease Models, Animal
  • Mice
  • Mice, Transgenic
  • Microglia / metabolism
  • Neurodegenerative Diseases* / pathology
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / genetics
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / metabolism
  • Plaque, Amyloid / pathology
  • Risk Factors


  • Amyloid beta-Peptides
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases