Encouraged by our mechanistic studies demonstrating the critical role of the PKCι/λ-βARR2 axis in disrupting the SORLA-retromer interaction and promoting SORLA lysosomal trafficking and degradation (illustrated in Fig. 5J), we sought to determine whether inhibiting this kinase could increase SORLA levels and subsequently reduce Aβ pathology and cognitive deficits in an AD mouse model, AppNL−G−F/NL−G−F (referred to as AppKI) mice. Here, ARRB2 is linked to Alzheimer disease.