A Target Enablement Package for the Inhibition of SHIP1 as a Therapeutic Strategy for the Treatment of Alzheimer’s Disease

Recent evidence including GWAS and differential gene expression comparing normal to affected Alzheimer’s brain tissue have identified risk and protective variants in genes such as TREM2, PLCG2 and INPP5D that are essential to microglia function. INPP5D encodes SHIP1, a multi‐domain protein with a phosphatase that converts PI(3,4,5)P3 to PI(3,4)P2, a SH2 domain that interacts with receptor ITAMs and competes with SYK, and a proline rich region that binds many other proteins. SHIP1 therefore limits microglia activation in multiple ways. Inhibition of SHIP1 early in disease would increase microglial protective functions and reduce the rate of disease progression and cognitive decline in Alzheimer’s patients.