{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T12:35:41Z","timestamp":1785760541243,"version":"3.56.0"},"reference-count":46,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T00:00:00Z","timestamp":1754870400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01AG048172"],"award-info":[{"award-number":["R01AG048172"]}]},{"name":"NIH","award":["P30-AG062715"],"award-info":[{"award-number":["P30-AG062715"]}]},{"name":"NIH","award":["P30 EY016665"],"award-info":[{"award-number":["P30 EY016665"]}]},{"name":"Hilldale Undergraduate\/Faculty Research Fellowship","award":["R01AG048172"],"award-info":[{"award-number":["R01AG048172"]}]},{"name":"Hilldale Undergraduate\/Faculty Research Fellowship","award":["P30-AG062715"],"award-info":[{"award-number":["P30-AG062715"]}]},{"name":"Hilldale Undergraduate\/Faculty Research Fellowship","award":["P30 EY016665"],"award-info":[{"award-number":["P30 EY016665"]}]},{"name":"University of Wisconsin Alzheimer\u2019s Disease Research Center","award":["R01AG048172"],"award-info":[{"award-number":["R01AG048172"]}]},{"name":"University of Wisconsin Alzheimer\u2019s Disease Research Center","award":["P30-AG062715"],"award-info":[{"award-number":["P30-AG062715"]}]},{"name":"University of Wisconsin Alzheimer\u2019s Disease Research Center","award":["P30 EY016665"],"award-info":[{"award-number":["P30 EY016665"]}]},{"name":"UW Fall competition award","award":["R01AG048172"],"award-info":[{"award-number":["R01AG048172"]}]},{"name":"UW Fall competition award","award":["P30-AG062715"],"award-info":[{"award-number":["P30-AG062715"]}]},{"name":"UW Fall competition award","award":["P30 EY016665"],"award-info":[{"award-number":["P30 EY016665"]}]},{"name":"Core Grant for Vision Research from the NIH to the University of Wisconsin-Madison","award":["R01AG048172"],"award-info":[{"award-number":["R01AG048172"]}]},{"name":"Core Grant for Vision Research from the NIH to the University of Wisconsin-Madison","award":["P30-AG062715"],"award-info":[{"award-number":["P30-AG062715"]}]},{"name":"Core Grant for Vision Research from the NIH to the University of Wisconsin-Madison","award":["P30 EY016665"],"award-info":[{"award-number":["P30 EY016665"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Tau aggregation and the subsequent formation of neurofibrillary tangles are hallmarks of Alzheimer\u2019s disease (AD) and other dementias. While accumulation of tau aggregates is believed to contribute to cell death and neurodegeneration, tau aggregation and hyperphosphorylation are also correlated with cognitive impairment in AD. To understand the role of tau in neurodegeneration, we used adeno-associated virus serotype 9 (AAV9) to express human wild-type 4-repeat, 0-N-terminus tau isoform (AAV-htau) in the Cornu ammonis area 1 (CA1) region of the dorsal hippocampus of adult 6-month-old Fischer 344 rats. AAV expressing green fluorescent protein (AAV-GFP) or uninjected rats were used as controls. To characterize early phenotypes, we investigated pathological changes at 3, 8, and 12 weeks post-injection of AAV-htau. Our results show that at 3 weeks post-injection, there was already robust expression of human tau in the CA1 region of animals injected with AAV-htau compared to those injected with AAV-GFP or the uninjected controls. At 12 weeks post-injection, area CA1 showed a statistically significant reduction in cell number and a thinner neuronal layer all throughout the anterior dorsal hippocampus, as well as redistribution to the somatodendritic areas of CA1. We also found hyperphosphorylation of tau at all three timepoints. In spite of this pathology, we did not find any hippocampal-dependent cognitive impairment in rats overexpressing human tau. These results provide evidence of AAV-htau as a progressive model of tauopathy pathology to study changes in phosphorylation status and neuronal cell death that might precede cognitive impairment.<\/jats:p>","DOI":"10.3390\/cells14161238","type":"journal-article","created":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T09:59:13Z","timestamp":1754906353000},"page":"1238","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Adeno-Associated Viral Gene Delivery of Wild-Type Human Tau Induces Progressive Hyperphosphorylation and Neuronal Cell Death in the Hippocampi of Middle-Aged Rats"],"prefix":"10.3390","volume":"14","author":[{"given":"Ryan C.","family":"Gorzek","sequence":"first","affiliation":[{"name":"Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA"},{"name":"College of Letters and Science, University of Wisconsin-Madison, Madison, WI 53706, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurelie","family":"Joly-Amado","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL 33620, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2610-5797","authenticated-orcid":false,"given":"Natalia","family":"Hurst-Calle","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL 33620, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham L.","family":"Gabrielson","sequence":"additional","affiliation":[{"name":"College of Letters and Science, University of Wisconsin-Madison, Madison, WI 53706, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxine","family":"Miller","sequence":"additional","affiliation":[{"name":"College of Letters and Science, University of Wisconsin-Madison, Madison, WI 53706, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sue","family":"Osting","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8607-1832","authenticated-orcid":false,"given":"Kevin R.","family":"Nash","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL 33620, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9432-0114","authenticated-orcid":false,"given":"Corinna","family":"Burger","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4913","DOI":"10.1073\/pnas.83.13.4913","article-title":"Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology","volume":"83","author":"Iqbal","year":"1986","journal-title":"Proc. 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