The Alzheimer’s Disease Risk Factor INPP5D Restricts Neuroprotective Microglial Responses in Amyloid Beta-Mediated Pathology

Authors

Joshua D Samuels
Katelyn A Moore
Hannah E Ennerfelt
Alexis M Johnson
Adeline E Walsh
Richard J Price
John R Lukens

Publication Date

11-1-2023

Journal

Alzheimer's & Dementia

Abstract

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 Inpp5d

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 Inpp5d

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, microglia, SHIP-1, INPP5D, amyloid beta, amyloidosis, neuroimmunology, disease-associated microglia, neurodegenerative disease

Comments

Supplementary Materials

PMID: 37061460