INPP5D modulates TREM2 loss-of-function phenotypes in a ß-amyloidosis mouse model

We crossed Tyrobp-deficient and Inpp5d-deficient mice with App(NL-G-F/NL-G-F) Alzheimer model mice (hereafter, NLGF) and generate Tyrobp-/-;Inpp5d+/-;NLGF mice to assess the role of Inpp5d in Tyrobp-/- mice. We isolated microglia from NLGF, Tyrobp-/-;NLGF, and Tyrobp-/-;Inpp5d+/-;NLGF mice and analyzed microglial transcriptome using RNA-sequencing. Tyrobp-/- microglia showed substantially different transcriptome compared with NLGF microglia. Previously described "disease asscociated microglia" genes were enriched in the differentially expressed genes in Tyrobp-/- microglia. On the other hand, Tyrobp-/-;Inpp5d+/-;NLGF microglia showed similar transcriptome to Tyrobp-/- microglia except several genes (e.g., Wdfy1, Mamdc2, Klrb1f). These data suggest Inpp5d modulates microglial functions without affecting disease associated microglial gene expression in Tyrobp-/-;NLGF micrglia. Overall design: Microglial transcriptome of 9-month-old NLGF (N=3), Inpp5d+/-;NLGF (N=3), Tyrobp-/-;NLGF (N=2), Tyrobp-/-;Inpp5d+/-;NLGF (N=3) mice. CD11b+/CD45+ live cells were collected as microglia.