Characterization of cellular responses of Ptpn6 (SHP-1) cKO in hippocampus by scRNA-seq

Ptpn6 (SHP-1) is known to impact signaling pathways in immune cells in various different ways, and in many cases, SHP1 opposes immune cell activation by nonreceptor tyrosine kinases such as Syk, Jak or ZAP70. In Alzheimer’s disease, multiple AD risk genes are expressed in microglia and related to microglial regulation and function. SHP-1 interacts with ITIM domains of multiple AD GWAS genes including Siglec-11, LILRB2, PILRA, and CD33 and SHP-1 is also known as a negative regulator of DAP12/Trem2 signaling. To understand cellular pathways of ITIM signaling and delineate benefits and liabilities of ITIM signaling inhibition, here we characterize Ptpn6 cKO (Cohort I) and Ptpn6 cKO crossed with previously characterized AD mouse model TauPS2APP (Cohort II) by single cell RNA-seq. We found that Ptpn6 deletion unleashes disease-like transcriptional changes in vivo. We also discovered distinct microglia activation states associated with protective versus exacerbative Ptpn6 genotypes. Current scRNA-seq results reveal both protective and latent degenerative potential of microglia held in check by Ptpn6.