DSCR1 deficiency ameliorates the Aβ pathology of Alzheimer's disease by enhancing microglial activity

Microglial phagocytosis and clearance are important for the removal of amyloid-beta (A beta) plaques in Alzheimer's disease (AD). Chronic exposure of microglia to A beta plaques leads to microglial metabolic dysfunction, and dysregulation of microglia can accelerate the deposition of A beta plaques and cause learning and memory impairment. Thus, regulating microglial A beta clearance is crucial for the development of therapeutics for AD-related dementia. Here, Down syndrome critical region 1 (DSCR1) deficiency ameliorated A beta plaque deposition in the 5xFAD mouse model of AD by altering microglial activity; however, the A beta synthesis pathway was not affected. DSCR1 deficiency improved spatial learning and memory impairment in 5xFAD mice. Furthermore, DSCR1-deficient microglia exhibited accelerated lysosomal degradation of A beta after phagocytosis, and BV2 cells with stable knockdown of DSCR1 demonstrated enhanced lysosomal activity. RNA-sequencing analysis showed that the transcriptional signatures associated with responses to IFN-gamma were significantly upregulated in DSCR1-knockdown BV2 cells treated with AP. Our data strongly suggest that DSCR1 is a critical mediator of microglial degradation of amyloid plaques and a new potential microglial therapeutic target in AD.