{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T00:44:38Z","timestamp":1780101878902,"version":"3.54.0"},"posted":{"date-parts":[[2025,2,17]]},"group-title":"Neuroscience","reference-count":70,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T00:00:00Z","timestamp":1739750400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,3,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Despite recent approval of monoclonal antibodies that reduce amyloid (A\u03b2) accumulation, the development of disease-modifying strategies targeting the underlying mechanisms of Alzheimer\u2019s disease (AD) is urgently needed. We demonstrate that mitochondrial complex I (mtCI) represents a druggable target, where its weak inhibition activates neuroprotective signaling, benefiting AD mouse models with A\u03b2 and p-Tau pathologies. Rational design and structure\u2012activity relationship studies yielded novel mtCI inhibitors profiled in a drug discovery funnel designed to address their safety, selectivity, and efficacy. The new lead compound C458 is highly protective against A\u03b2 toxicity, has favorable pharmacokinetics, and has minimal off-target effects. C458 exhibited excellent brain penetrance, activating neuroprotective pathways with a single dose. Preclinical studies in APP\/PS1 mice were conducted via functional tests, metabolic assessment,\n                  <jats:italic>in vivo<\/jats:italic>\n                  <jats:sup>31<\/jats:sup>\n                  P- NMR spectroscopy, blood cytokine panels,\n                  <jats:italic>ex vivo<\/jats:italic>\n                  electrophysiology, and Western blotting. Chronic oral administration improved long-term potentiation, reduced oxidative stress and inflammation, and enhanced mitochondrial biogenesis, antioxidant signaling, and cellular energetics. These studies provide further evidence that the restoration of mitochondrial function and brain energetics in response to mild energetic stress represents a promising disease- modifying strategy for AD.\n                <\/jats:p>","DOI":"10.1101\/2025.02.12.637918","type":"posted-content","created":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T20:10:39Z","timestamp":1739823039000},"source":"Crossref","is-referenced-by-count":2,"title":["Therapeutic assessment of a novel mitochondrial complex I inhibitor in\n                  <i>in vitro<\/i>\n                  and\n                  <i>in vivo<\/i>\n                  models of Alzheimer\u2019s disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0470-6345","authenticated-orcid":false,"given":"Sergey","family":"Trushin","sequence":"first","affiliation":[{"name":"Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6068-6222","authenticated-orcid":false,"given":"Thi Kim Oanh","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0046-7033","authenticated-orcid":false,"given":"Andrea","family":"Stojacovic","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1253-2120","authenticated-orcid":false,"given":"Mark","family":"Ostroot","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5361-7714","authenticated-orcid":false,"given":"J. Trey","family":"Deason","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8373-8921","authenticated-orcid":false,"given":"Su-Youne","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Neurologic Surgery, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA"},{"name":"Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9463-3241","authenticated-orcid":false,"given":"Liang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6054-5163","authenticated-orcid":false,"given":"Slobodan I.","family":"Macura","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3107-0680","authenticated-orcid":false,"given":"Toshihiko","family":"Nambara","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9803-5162","authenticated-orcid":false,"given":"Wenyan","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6751-9374","authenticated-orcid":false,"given":"Takahisa","family":"Kanekiyo","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6291-2860","authenticated-orcid":false,"given":"Eugenia","family":"Trushina","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA"},{"name":"Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041110241018000_2025.02.12.637918v2.1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-023-00783-1"},{"key":"2026041110241018000_2025.02.12.637918v2.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2023.01.008"},{"key":"2026041110241018000_2025.02.12.637918v2.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01547-9"},{"key":"2026041110241018000_2025.02.12.637918v2.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-020-0072-x"},{"key":"2026041110241018000_2025.02.12.637918v2.5","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-161088"},{"key":"2026041110241018000_2025.02.12.637918v2.6","doi-asserted-by":"publisher","DOI":"10.1016\/S1534-5807(01)00071-5"},{"key":"2026041110241018000_2025.02.12.637918v2.7","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M403066200"},{"key":"2026041110241018000_2025.02.12.637918v2.8","doi-asserted-by":"publisher","DOI":"10.1126\/science.1077780"},{"key":"2026041110241018000_2025.02.12.637918v2.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2011.12.005"},{"key":"2026041110241018000_2025.02.12.637918v2.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2017.08.018"},{"key":"2026041110241018000_2025.02.12.637918v2.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.09.070"},{"key":"2026041110241018000_2025.02.12.637918v2.12","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(98)07037-8"},{"key":"2026041110241018000_2025.02.12.637918v2.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2015.03.009"},{"key":"2026041110241018000_2025.02.12.637918v2.14","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-020-01584-y"},{"key":"2026041110241018000_2025.02.12.637918v2.15","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-201015"},{"key":"2026041110241018000_2025.02.12.637918v2.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2008.12.060"},{"key":"2026041110241018000_2025.02.12.637918v2.17","doi-asserted-by":"crossref","unstructured":"Panes J , Nguyen TKO , Gao H , et al. 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