{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T23:29:40Z","timestamp":1793316580126,"version":"4.5.0"},"reference-count":72,"publisher":"American Society for Clinical Investigation","issue":"1","license":[{"start":{"date-parts":[[2025,1,2]],"date-time":"2025-01-02T00:00:00Z","timestamp":1735776000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["32371030,82371194,82071395"],"award-info":[{"award-number":["32371030,82371194,82071395"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100005230","name":"the Natural Science Foundation of Chongqing","doi-asserted-by":"crossref","award":["CSTB2022NSCQ-LZX0010,CSTB2024NSCQ-LZX0008"],"award-info":[{"award-number":["CSTB2022NSCQ-LZX0010,CSTB2024NSCQ-LZX0008"]}],"id":[{"id":"10.13039\/501100005230","id-type":"DOI","asserted-by":"crossref"}]},{"name":"the CQMU Program for Youth Innovation in Future Medicine","award":["W0044"],"award-info":[{"award-number":["W0044"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,1,2]]},"abstract":"<jats:p>\n                    Posttranslational modification (PTM) of the amyloid precursor protein (APP) plays a critical role in Alzheimer\u2019s disease (AD). Recent evidence reveals that lactylation modification, as a novel PTM, is implicated in the occurrence and development of AD. However, whether and how APP lactylation contributes to both the pathogenesis and cognitive function in AD remains unknown. Here, we observed a reduction in APP lactylation in AD patients and AD model mice and cells. Proteomic mass spectrometry analysis further identified lysine 612 (APP-K612la) as a crucial site for APP lactylation, influencing APP amyloidogenic processing. A lactyl-mimicking mutant (APP\n                    <jats:sub>K612T<\/jats:sub>\n                    ) reduced amyloid-\u03b2 peptide (A\u03b2) generation and slowed down cognitive deficits in vivo. Mechanistically, APP\n                    <jats:sub>K612T<\/jats:sub>\n                    appeared to facilitate APP trafficking and metabolism. However, lactylated APP entering the endosome inhibited its binding to BACE1, suppressing subsequent cleavage. Instead, it promoted protein interaction between APP and CD2-associated protein (CD2AP), thereby accelerating the endosomal-lysosomal degradation pathway of APP. In the APP23\/PS45 double-transgenic mouse model of AD, APP-Kla was susceptible to L-lactate regulation, which reduced A\u03b2 pathology and repaired spatial learning and memory deficits. Thus, these findings suggest that targeting APP lactylation may be a promising therapeutic strategy for AD in humans.\n                  <\/jats:p>","DOI":"10.1172\/jci184656","type":"journal-article","created":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T14:00:42Z","timestamp":1735740042000},"source":"Crossref","is-referenced-by-count":57,"title":["APP lysine 612 lactylation ameliorates amyloid pathology and memory decline in Alzheimer\u2019s disease"],"prefix":"10.1172","volume":"135","author":[{"given":"Qiuyun","family":"Tian","sequence":"first","affiliation":[{"name":"Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children\u2019s Hospital of Chongqing Medical University, Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjie","family":"Li","sequence":"additional","affiliation":[{"name":"Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children\u2019s Hospital of Chongqing Medical University, Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Wu","sequence":"additional","affiliation":[{"name":"Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, 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Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children\u2019s Hospital of Chongqing Medical University, Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Xiao","sequence":"additional","affiliation":[{"name":"Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children\u2019s Hospital of Chongqing Medical University, Chongqing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaojiao","family":"Wang","sequence":"additional","affiliation":[{"name":"Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National 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