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

• Published in: Alzheimer's & dementia Vol. 19; no. 11; pp. 4908 - 4921
• Main Authors: Samuels, Joshua D, Moore, Katelyn A, Ennerfelt, Hannah E, Johnson, Alexis M, Walsh, Adeline E, Price, Richard J, Lukens, John R
• Format: Journal Article
• Language: English
• Published: United States 01.11.2023
• Subjects: 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; neuroimmunology; amyloidosis; neurodegenerative disease; disease-associated microglia; INPP5D; SHIP-1; Alzheimer's disease; microglia; amyloid beta
• ISSN: 1552-5260; 1552-5279; 1552-5279
• DOI: 10.1002/alz.13089

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. We generated and investigated 5xFAD Inpp5d Cx3cr1 mice to ascertain the function of microglial SHIP-1 signaling in response to amyloid beta (Aβ)-mediated pathology. 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 Inpp5d littermate controls. 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. 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.