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We assessed transcriptomic alterations in the brains of\n                      <jats:italic>Ndufs4<\/jats:italic>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      mice, a model of mitochondrial complex I (mtCI) deficiency, and evaluated the therapeutic effects of the neuroprotective mtCI inhibitor CP2.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      Cortico\u2010hippocampal tissue from\n                      <jats:italic>\n                        Ndufs4\n                        <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      <\/jats:italic>\n                      and wild\u2010type mice was subjected to transcriptomic analysis, followed by cross\u2010species comparisons to human late\u2010onset AD and familial AD mouse datasets.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Knockout of\n                      <jats:italic>Ndufs4<\/jats:italic>\n                      \u2010mediated mtCI deficiency disrupted mitochondrial homeostasis, energy metabolism, and synaptic gene expression, recapitulating transcriptomic signatures of AD. CP2 treatment partially reversed these changes, with female\n                      <jats:italic>Ndufs4<\/jats:italic>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      mice showing greater compensatory adaptations and treatment responses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>Loss of mtCI activity alone is sufficient to induce AD\u2010like molecular changes in the brain, independent of amyloid beta or phosphorylated tau. CP2\u2010mediated rescue highlights the potential of targeting mitochondria as a therapeutic strategy for AD. Sex\u2010specific responses suggest important considerations for personalized therapeutics.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Activity of mitochondrial complex I (mtCI) affects broad mitochondrial and neuronal transcriptional networks.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>A reduction of mtCI activity is sufficient to induce transcriptomic changes reminiscent of those observed in late\u2010onset Alsheimer's disease (AD) patients and familial mouse models of AD.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Pharmacological targeting of mtCI mediates neuroprotective signaling.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Male and female mice have differential responses to the loss of mtCI activity and to the mitochondria\u2010targeted therapeutics.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Mitochondria play a key role in AD development and treatment.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.70519","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T03:08:52Z","timestamp":1753844932000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Mitochondrial complex I deficiency induces Alzheimer's disease\u2013like signatures that 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