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Alliance"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:p>Microglial phagocytosis and clearance are important for the removal of amyloid-\u03b2 (A\u03b2) plaques in Alzheimer\u2019s disease (AD). Chronic exposure of microglia to A\u03b2 plaques leads to microglial metabolic dysfunction, and dysregulation of microglia can accelerate the deposition of A\u03b2 plaques and cause learning and memory impairment. Thus, regulating microglial A\u03b2 clearance is crucial for the development of therapeutics for AD-related dementia. Here, Down syndrome critical region 1 (DSCR1) deficiency ameliorated A\u03b2 plaque deposition in the 5xFAD mouse model of AD by altering microglial activity; however, the A\u03b2 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\u03b2 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-\u03b3 were significantly up-regulated in DSCR1-knockdown BV2 cells treated with A\u03b2. 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.<\/jats:p>","DOI":"10.26508\/lsa.202201556","type":"journal-article","created":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T18:20:22Z","timestamp":1669832422000},"page":"e202201556","update-policy":"https:\/\/doi.org\/10.26508\/lsa.crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["DSCR1 deficiency ameliorates the A\u03b2 pathology of Alzheimer\u2019s disease by enhancing microglial activity"],"prefix":"10.26508","volume":"6","author":[{"given":"Chiyeol","family":"Choi","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, College of Information and Bioengineering, Ulsan National Institute of Science and Technology, Ulsan, Republic of 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