{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:22:46Z","timestamp":1785424966433,"version":"3.56.0"},"posted":{"date-parts":[[2026,5,14]]},"group-title":"Neuroscience","reference-count":50,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R01NS095969"],"award-info":[{"award-number":["R01NS095969"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R33\/R61NS115161"],"award-info":[{"award-number":["R33\/R61NS115161"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["UG3\/UH3R61NS115608161"],"award-info":[{"award-number":["UG3\/UH3R61NS115608161"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  While most Alzheimer\u2019s disease (AD) which is associated with\n                  <jats:underline>L<\/jats:underline>\n                  imbic\n                  <jats:underline>P<\/jats:underline>\n                  redominant\n                  <jats:underline>A<\/jats:underline>\n                  ge-related\n                  <jats:underline>T<\/jats:underline>\n                  DP-43\n                  <jats:underline>E<\/jats:underline>\n                  ncephalopathy (LATE) exhibits accelerated brain atrophy, the pathogenic mechanism remains elusive. We show here, in mice harboring depositions of amyloid-\u03b2 and tau, the age-dependent emergence of TDP-43 proteinopathy. We demonstrate that TDP-43 dysfunction facilitates caspase 3-mediated endoproteolysis of tau, accelerates tauopathy and exacerbates neuron loss. Unexpectedly, we found that the emergence and spread of TDP-43 proteinopathy is associated with the spread of tauopathy and correlated with co-filament assembly of tau and TDP-43. Importantly, TDP-43 dysfunction precedes such co-filament assembly and TDP-43 cytoplasmic aggregates. Consistent with the idea that tauopathy could prime co-filament assembly and proteinopathy of TDP-43 to exacerbate neurodegeneration, we found tau co-filament assembly with TDP-43 in AD and AD-LATE cases. These findings suggest that TDP-43 dysfunction accelerates tauopathy, which, in turn, primes co-filament assembly and dysfunction of TDP-43 to exacerbate neuron loss in AD-LATE, a pathogenic mechanism disclosing novel targets and therapeutic strategies.\n                <\/jats:p>","DOI":"10.64898\/2026.05.11.723888","type":"posted-content","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T18:30:14Z","timestamp":1778783414000},"source":"Crossref","is-referenced-by-count":1,"title":["Tauopathy primes co-filament assembly and dysfunction of TDP-43"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3988-6438","authenticated-orcid":false,"given":"Meghraj S.","family":"Baghel","sequence":"first","affiliation":[{"name":"Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8691-779X","authenticated-orcid":false,"given":"Grace D.","family":"Burns","sequence":"additional","affiliation":[{"name":"Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0303-5156","authenticated-orcid":false,"given":"Aswathy Peethambaran","family":"Mallika","sequence":"additional","affiliation":[{"name":"Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7294-4008","authenticated-orcid":false,"given":"Xiaoke K.","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangbing","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6079-1138","authenticated-orcid":false,"given":"Shruti","family":"Renganathan","sequence":"additional","affiliation":[{"name":"Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9553-6673","authenticated-orcid":false,"given":"Juan C.","family":"Troncoso","sequence":"additional","affiliation":[{"name":"Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA"},{"name":"Department of Neurology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8162-3274","authenticated-orcid":false,"given":"Philip C.","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA"},{"name":"Department of Neuroscience, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, 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