{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T16:44:05Z","timestamp":1787244245227,"version":"build-2736575974"},"reference-count":88,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Alzheimer\u2019s disease (AD) is the most common form of dementia, characterized by progressive memory decline, with neuropathological hallmarks including amyloid plaques and neurofibrillary tangles. Current treatments only alleviate symptoms and cannot halt disease progression. Icaritin (ICT), a natural compound, has shown neuroprotective potential. Transactive response DNA-binding protein 43 (TDP-43) is widely recognized as a key neuropathological hallmark of AD and related dementias. This study investigated the protective effects of ICT against TDP-43-induced damage in N2a\/APP695swe (APP) cells and explored the underlying mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>N2a\/APP695swe\/TARDBP cells overexpressing APP and TDP-43 were constructed via lentiviral transfection, and the optimal ICT dosage was determined using the CCK-8 assay. The effects of ICT on TDP-43 cell phenotypes were then assessed using CCK-8, ELISA, and Western blot. Finally, transmission electron microscopy, flow cytometry, assay kits, and Western blot were used to investigate the protective mechanisms of ICT.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>ICT treatment significantly increased cell viability, reduced A\u03b242 levels, and alleviated phospho-Tau and phospho-TDP-43 accumulation. Mechanistically, ICT improved mitochondrial morphology, decreased ROS levels, enhanced ATP production, and modulated the AMPK\/mTOR and PINK1\/Parkin autophagy signaling pathways to mitigate TDP-43-mediated cellular stress.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>ICT protects cells from TDP-43-induced mitochondrial dysfunction and autophagy impairment, providing mechanistic insight into its potential as a therapeutic agent for AD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnagi.2026.1741339","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T05:29:57Z","timestamp":1773120597000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Icaritin ameliorates mitochondrial dysfunction and autophagy impairment in cellular models of Alzheimer\u2019s disease"],"prefix":"10.3389","volume":"18","author":[{"given":"Lingqiong","family":"Xia","sequence":"first","affiliation":[{"name":"Department of Neurology, The Third Affiliated Hospital of Zunyi Medical University (The First People\u2019s Hospital of Zunyi)","place":["Zunyi, Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The Third Affiliated Hospital of Zunyi Medical University (Zunyi First People's Hospital)","place":["Zunyi, Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengping","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Third Affiliated Hospital of Zunyi Medical University (The First People\u2019s Hospital of Zunyi)","place":["Zunyi, Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianfa","family":"Ao","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Third Affiliated Hospital of Zunyi Medical University (The First People\u2019s Hospital of Zunyi)","place":["Zunyi, Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Chen","sequence":"additional","affiliation":[{"name":"Longnan Hospital, The First Affiliated Hospital of Gannan Medical University (Longnan First People\u2019s Hospital)","place":["Ganzhou, Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Third Affiliated Hospital of Zunyi Medical University (The First People\u2019s Hospital of Zunyi)","place":["Zunyi, Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianfeng","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, The Third Affiliated Hospital of Zunyi Medical University (Zunyi First People's Hospital)","place":["Zunyi, Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nanqu","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Third Affiliated Hospital of Zunyi Medical University (The First People\u2019s Hospital of Zunyi)","place":["Zunyi, Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Third Affiliated Hospital of Zunyi Medical University (The First People\u2019s Hospital of Zunyi)","place":["Zunyi, Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,10]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1128\/MCB.06159-11","article-title":"Role of AMPK-mTOR-Ulk1\/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks","volume":"32","author":"Alers","year":"2012","journal-title":"Mol. 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