{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T06:28:53Z","timestamp":1789885733543,"version":"4.0.1"},"reference-count":54,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"21","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2025,5,23]]},"abstract":"<jats:p>\n            \u03b2-Site amyloid precursor protein (APP)\u2013cleaving enzyme 1 (BACE1) is the rate-limiting enzyme for amyloid-\u03b2 (A\u03b2) generation and is considered promising drug target for Alzheimer\u2019s disease (AD). The co-chaperone BAG3 (Bcl-2\u2013associated athanogene 3) plays an important role in maintaining intracellular protein homeostasis by regulating heat shock protein 70 (HSP70). Here, we reported that BAG3 expression was significantly elevated in AD. It interacted with and stabilized BACE1 by delaying its degradation through ubiquitin-proteasome and autophagy-lysosomal pathways. BAG3\n            <jats:sup>E455K<\/jats:sup>\n            and BAG3\n            <jats:sup>R480A<\/jats:sup>\n            mutations reduced their interaction with BACE1. SPOT peptide arrays revealed that BACE1 carboxyl-terminal peptide fragments bound to the RQ domain of BAG3. This interaction can be disrupted by BACE1-derived peptide (Tat-BACE1\n            <jats:sub>480-494<\/jats:sub>\n            ), leading to decreased BACE1 stability. In APP23\/PS45 double transgenic mice, Tat-BACE1\n            <jats:sub>480-494<\/jats:sub>\n            reduced BACE1 levels, decreased A\u03b2 production, and improved synaptic and cognitive deficits. These findings indicate that BAG3 forms complex with HSP70 and BACE1 to stabilize BACE1, suggesting that Tat-BACE1\n            <jats:sub>480-494<\/jats:sub>\n            , may represent an ideal class of neuroprotective therapeutics against AD.\n          <\/jats:p>","DOI":"10.1126\/sciadv.adt7981","type":"journal-article","created":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T14:00:21Z","timestamp":1748008821000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":6,"title":["Disruption of BAG3-mediated BACE1 stabilization alleviates neuropathology and memory deficits in a mouse model of Alzheimer\u2019s disease"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8527-6107","authenticated-orcid":true,"given":"Lei","family":"Xia","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 400014, 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 400014, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3691-9309","authenticated-orcid":true,"given":"Yayan","family":"Pang","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 400014, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunfang","family":"Dai","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 400014, China."},{"name":"Department of Children Health Care, Guangzhou Women and Children\u2019s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510623, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingliang","family":"Xu","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 400014, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yehong","family":"Du","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 400014, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuyun","family":"Tian","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 400014, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilin","family":"Yi","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 400014, 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, Children\u2019s Hospital of Chongqing Medical University, Chongqing 400014, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0520-4223","authenticated-orcid":true,"given":"Mulan","family":"Chen","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 400014, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0648-3949","authenticated-orcid":true,"given":"Yiqiong","family":"Qiu","sequence":"additional","affiliation":[{"name":"Clinical Laboratory of Changshou District Hospital of Traditional Chinese Medicine, Chongqing 401220, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0680-2448","authenticated-orcid":true,"given":"Chongjie","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8592-0698","authenticated-orcid":true,"given":"Yu Tian","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Brain Research Centre, Vancouver Coastal Health Research Institute, University of British 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