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Pericyte degeneration and blood\u2013brain barrier (BBB) disruption are thought to be early biomarkers of AD and contribute to cognitive decline in\n                      <jats:italic>APOE4<\/jats:italic>\n                      carriers, representing potential therapeutic targets. Our previous studies have shown that pericyte transplantation is one of the most effective strategies for BBB restoration, exhibiting great therapeutic potential for\n                      <jats:italic>APOE4<\/jats:italic>\n                      -related BBB damage and AD phenotypes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      <jats:italic>APOE<\/jats:italic>\n                      4\/4 mice were treated with pericytes derived from\n                      <jats:italic>APOE<\/jats:italic>\n                      3\/3 human induced pluripotent stem cells (hiPSCs). Behavioral tests, AD pathologies, and BBB integrity were assessed. Subsequently, temporal and spatial distribution of the transplanted pericytes was analyzed using tdTomato\n                      <jats:sup>+<\/jats:sup>\n                      lentivirus labeling. Next, therapeutic effects of apoptotic vesicles (ApoVs) generated from\n                      <jats:italic>APOE<\/jats:italic>\n                      3\/3 pericytes were evaluated in\n                      <jats:italic>APOE<\/jats:italic>\n                      4\/4 pericytes in vitro. Additionally, transcriptomic and proteomic profiling were performed to identify key effector molecules in pericyte-derived ApoVs. Finally, the therapeutic effects of ApoVs derived from pericytes were evaluated in\n                      <jats:italic>APOE<\/jats:italic>\n                      4\/4 mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Early, multiple transplantations of pericytes derived from\n                      <jats:italic>APOE<\/jats:italic>\n                      3\/3 hiPSCs robustly rescued cognitive decline and AD pathologies, restored BBB integrity, and prevented in situ pericyte degeneration in aged\n                      <jats:italic>APOE<\/jats:italic>\n                      4\/4 mice. Intriguingly, ApoVs released from the infused cells, rather than the transplanted pericytes, were predominantly distributed in the brain, which were ingested by in situ\n                      <jats:italic>APOE<\/jats:italic>\n                      4\/4 pericytes and then promoted functional recovery. We further characterized insulin growth factor-2 (IGF-2) as a key factor in\n                      <jats:italic>APOE<\/jats:italic>\n                      3\/3 pericyte-derived ApoVs. Infusion of the in vitro generated ApoVs from\n                      <jats:italic>APOE<\/jats:italic>\n                      3\/3 pericytes demonstrated distinct therapeutic effects in\n                      <jats:italic>APOE<\/jats:italic>\n                      4\/4 mice, which were reversed by IGF2 knockout.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      <jats:italic>APOE<\/jats:italic>\n                      3\/3 pericytes or\n                      <jats:italic>APOE<\/jats:italic>\n                      3\/3 pericyte-derived IGF2-rich ApoVs may offer promising therapeutic strategies for\n                      <jats:italic>APOE<\/jats:italic>\n                      4-associated AD.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s40035-025-00512-6","type":"journal-article","created":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T01:36:49Z","timestamp":1762997809000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Transplantation of hiPSC-derived pericytes rescues Alzheimer\u2019s disease phenotypes in APOE4\/4 mice through IGF2-rich apoptotic vesicles"],"prefix":"10.1186","volume":"14","author":[{"given":"Chuanfeng","family":"Xiong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junhua","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingming","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoran","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingqiang","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuejiao","family":"Men","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiumin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dairui","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjin","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanchen","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijun","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengqi","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunfeng","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanming","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andy Peng","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4741-6778","authenticated-orcid":false,"given":"Weiqiang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,13]]},"reference":[{"key":"512_CR1","doi-asserted-by":"publisher","first-page":"1577","DOI":"10.1016\/S0140-6736(20)32205-4","volume":"397","author":"P Scheltens","year":"2021","unstructured":"Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chetelat G, Ce T, et al. 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