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This may potentially explain our previous paradoxical observation of elevated free-form p-tau217 alongside reduced p-tau217\n                      <jats:sup>+<\/jats:sup>\n                      EVs in plasma. This study aimed to investigate the mechanisms underlying the reduction of p-tau217\n                      <jats:sup>+<\/jats:sup>\n                      EVs to uncover AD therapeutic targets.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      By integrating hippocampal spatial transcriptomics of human brain with EV proteomics of cerebrospinal fluid, we identified key regulators of p-tau217\n                      <jats:sup>+<\/jats:sup>\n                      EV release. Subsequently, we investigated the mechanisms underlying the synthesis and secretion of p-tau217\n                      <jats:sup>+<\/jats:sup>\n                      EVs. The regulatory roles of these candidate proteins were systematically evaluated through shRNA knockdown and interference with a synthetic peptide in both A\u03b2\n                      <jats:sub>42<\/jats:sub>\n                      -treated cells and AD model mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Heat shock protein family A member 8 (HSPA8) was identified as a crucial regulator of EV biogenesis and release, mediating the A\u03b2\u2013SNAP29 interaction to disrupt SNARE complex assembly and impair p-tau217\n                      <jats:sup>+<\/jats:sup>\n                      EV secretion. In AD models, HSPA8 inhibition with shRNA rescued p-tau217\n                      <jats:sup>+<\/jats:sup>\n                      EVs and improved cognitive function. Additionally, blocking the A\u03b2\u2013SNAP29 interaction with a selective peptide inhibitor for HSPA8 reversed the decline in p-tau217\n                      <jats:sup>+<\/jats:sup>\n                      EV and cognitive deficits.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings reveal a role of HSPA8 in regulating the MVB-mediated EV release and tau propagation, and highlight HSPA8 as a promising therapeutic target for modifying AD progression.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s40035-026-00570-4","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T06:06:34Z","timestamp":1787810794000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["HSPA8 orchestrates SNARE complex assembly to drive extracellular vesicle-mediated spread of p-tau217 in Alzheimer's disease"],"prefix":"10.1186","volume":"15","author":[{"given":"Bin","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yazhou","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayi","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuoqing","family":"Lan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoping","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7222-8317","authenticated-orcid":false,"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"issue":"9770","key":"570_CR1","doi-asserted-by":"publisher","first-page":"1019","DOI":"10.1016\/S0140-6736(10)61349-9","volume":"377","author":"C Ballard","year":"2011","unstructured":"Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. 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The study was approved by the Human Ethics Committee of the School of Medicine, Zhejiang University (approval no. 2021-400). All animal procedures were approved by the Ethics Committee of the First Affiliated Hospital, Zhejiang University School of Medicine (approval no. 2021-667).","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"42"}}