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Yet the relationship between aCasp\u20106, different forms of tr\u2010tau and hyperphosphorylated tau (p\u2010tau) accumulation in human brains with Alzheimer's disease (AD) and other tauopathies remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We generated two neoepitope monoclonal antibodies against tr\u2010tau sites (D402 and D13) targeted by aCasp\u20106. Then, we used five\u2010plex immunofluorescence to quantify the neuronal and astroglial burden of aCasp\u20106, tr\u2010tau, p\u2010tau and their co\u2010occurrence in healthy controls, AD and primary tauopathies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Casp\u20106 activation was strongest in AD and Pick's disease (PiD) but almost absent in 4\u2010repeat (4R) tauopathies. In neurons, the tr\u2010tau burden was much more abundant in AD and PiD than in 4R tauopathies and disproportionally higher when normalising by p\u2010tau pathology. Tr\u2010tau astrogliopathy was detected in low numbers in 4R tauopathies. Unexpectedly, about half of tr\u2010tau positive neurons in AD and PiD lacked p\u2010tau aggregates, a finding we confirmed using several p\u2010tau antibodies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Early modulation of aCasp\u20106 to reduce tr\u2010tau pathology is a promising therapeutic strategy for AD and PiD but is unlikely to benefit 4R tauopathies. The large percentage of tr\u2010tau\u2010positive neurons lacking p\u2010tau suggests that many vulnerable neurons to tau pathology go undetected when using conventional p\u2010tau antibodies. Therapeutic strategies against tr\u2010tau pathology could be necessary to modulate the extent of tau abnormalities in AD. The disproportionally higher burden of tr\u2010tau in AD and PiD supports the development of biofluid biomarkers against tr\u2010tau to detect AD and PiD and differentiate them from 4R tauopathies at a patient level.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/nan.12819","type":"journal-article","created":{"date-parts":[[2022,5,4]],"date-time":"2022-05-04T21:44:08Z","timestamp":1651700648000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Caspase\u20106\u2010cleaved tau is relevant in Alzheimer's disease and marginal in four\u2010repeat tauopathies: Diagnostic and therapeutic implications"],"prefix":"10.1111","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9701-1352","authenticated-orcid":false,"given":"Panos","family":"Theofilas","sequence":"first","affiliation":[{"name":"Memory and Aging Center, UCSF Weill Institute for Neurosciences University of California San Francisco  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonia M. H.","family":"Piergies","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, UCSF Weill Institute for Neurosciences University of California San Francisco  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Oh","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, UCSF Weill Institute for Neurosciences University of California San Francisco  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoo Bin","family":"Lee","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, UCSF Weill Institute for Neurosciences University of California San Francisco  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song Hua","family":"Li","sequence":"additional","affiliation":[{"name":"Memory and Aging Center, UCSF Weill Institute for Neurosciences University of California San Francisco  San Francisco 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