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Microglial transcriptomic profiling was performed using single\u2010cell RNA sequencing (scRNA\u2010seq). A chaperone\u2010mediated autophagy\u2010targeting chimera (CMATAC) peptide was developed to degrade TMEM59, and its therapeutic efficacy was evaluated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Microglia\u2010specific TMEM59 ablation attenuated cognitive deficits, A\u03b2 plaque burden, and synapse loss in 5xFAD mice. TMEM59 deficiency reprogrammed disease\u2010associated microglia toward a highly phagocytic state. Mechanistically, TMEM59 deficiency enhanced microglial A\u03b2 phagocytosis in a triggering receptor expressed on myeloid cells 2 (TREM2)\u2010dependent manner, as it stabilized TREM2 protein, whereas loss of TREM2 abolished these protective effects. Treatment with the TMEM59\u2010degrading CMATAC peptide alleviated behavioral deficits and enhanced microglial A\u03b2 phagocytosis in 5xFAD mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>TMEM59 is a key regulator of microglial phagocytosis in AD and a novel target for amyloidosis intervention.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.71873","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:58:58Z","timestamp":1790315938000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["TMEM59 regulates microglial A\u03b2 phagocytosis in a TREM2\u2010dependent manner and acts as a potential therapeutic target for A\u03b2 amyloidosis"],"prefix":"10.1002","volume":"22","author":[{"given":"Jian","family":"Meng","sequence":"first","affiliation":[{"name":"Xiamen Key Laboratory of Brain Center, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine The First Affiliated Hospital of Xiamen University, Xiamen University  Xiamen Fujian China"},{"name":"Center for Geriatric Medicine, International Center for Alzheimer's Research, Prevention and Treatment, Oujiang Laboratory, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Institute of Aging The First Affiliated Hospital, Wenzhou Medical University  Wenzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Wang","sequence":"additional","affiliation":[{"name":"Xiamen Key Laboratory of Brain Center, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine The First 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