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We previously demonstrated that synapsin\u2010promoted caveolin\u20101 (\n                      <jats:italic>SynCav1<\/jats:italic>\n                      ) preserves cognitive function in the mouse model of AD. This study investigated the therapeutic potential of\n                      <jats:italic>SynCav1<\/jats:italic>\n                      in a mouse model of TDP\u201043 proteinopathy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      <jats:italic>AAV\u2010PhP.eB\u2010SynCav1<\/jats:italic>\n                      was delivered systemically to the TDP\u201043\n                      <jats:sup>A315T<\/jats:sup>\n                      mouse, followed by cognitive evaluation and biochemical and ultrastructural analysis of brain tissue.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      <jats:italic>SynCav1<\/jats:italic>\n                      exerted robust neuroprotective effects on cognition. Mechanistically, pathological TDP\u201043 mislocalized to membrane lipid rafts (MLRs), resulting in decreased MLR\u2010associated GluN2A expression and degenerative changes in neuronal ultrastructure. In contrast,\n                      <jats:italic>SynCav1<\/jats:italic>\n                      delivery alleviated TDP\u201043 mislocalization on MLRs, stabilized MLR\u2010associated GluN2A expression, and preserved synaptic ultrastructure. Furthermore,\n                      <jats:italic>SynCav1<\/jats:italic>\n                      mitigated TDP\u201043\u2013induced mitochondrial hyper\u2010fragmentation and excessive mitochondrial fission signaling.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>\n                      These findings establish a novel link between TDP\u201043 proteinopathy and MLR instability, supporting\n                      <jats:italic>SynCav1<\/jats:italic>\n                      as a \u201cneuron\u2010centric\u201d candidate for treating TDP\u201043\u2013related neurodegeneration.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.71450","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T11:00:07Z","timestamp":1779793207000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Systemic delivery of synapsin\u2010promoted caveolin\u20101 overexpression ameliorates pathological TDP\u201043\u2013induced cognitive decline and neurodegenerative changes"],"prefix":"10.1002","volume":"22","author":[{"given":"Dongsheng","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Anesthesiology University of California San Diego  La Jolla California USA"},{"name":"VA San Diego Healthcare System  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinh","family":"Ta","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology University of California San Diego  La Jolla California 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