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This study aimed to investigate the positive effects of NGR1 against cognitive deficits in a diabetic Alzheimer's disease (AD) mouse model (APP\/PS1x\n                    <jats:italic>db\/db<\/jats:italic>\n                    mice). APP\/PS1x\n                    <jats:italic>db\/db<\/jats:italic>\n                    mice were intragastrically administrated with NGR1 (40\u2009mg\/kg\/day) or co\u2010administrated with NGR1 and a selective PPAR\u03b3 inhibitor GW9662 for 16\u2009weeks. We identified NGR1 as a novel PPAR\u03b3 agonist through molecular docking, surface plasmon resonance, and dual\u2010luciferase reporter assay. NGR1 treatment significantly promoted the membrane translocation of GLUT4 and enhanced 2\u2010deoxyglucose uptake in primary mouse hippocampal neurons. Furthermore, NGR1 treatment notably mitigated cognitive deficits in APP\/PS1x\n                    <jats:italic>db\/db<\/jats:italic>\n                    mice. This treatment correlated with reduced blood glucose levels, lowered blood HbA1c, and decreased serum insulin levels, coupled with enhanced glucose tolerance and insulin sensitivity. Additionally, NGR1 treatment ameliorated A\u03b2 burden, suppressed microglia\u2010induced neuroinflammation, and notably increased cerebral glucose uptake, as demonstrated by\n                    <jats:sup>18<\/jats:sup>\n                    F\u2010FDG PET scans. NGR1 treatment could upregulate PPAR\u03b3 and GLUT4 expression and increase phosphorylation of Akt at Ser473 while decreasing phosphorylation of IRS\u20101 at Ser616 in the hippocampus of APP\/PS1x\n                    <jats:italic>db\/db<\/jats:italic>\n                    mice. Crucially, the protective effects of NGR1 were abolished by co\u2010administration with GW9662. NGR1 demonstrated efficacy in enhancing neuronal glucose uptake through the activation of the PPAR\u03b3\/Akt\/GLUT4 signaling pathways in APP\/PS1x\n                    <jats:italic>db\/db<\/jats:italic>\n                    mice, positioning it as a promising candidate for diabetic AD treatment.\n                  <\/jats:p>","DOI":"10.1002\/ptr.70006","type":"journal-article","created":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T09:29:19Z","timestamp":1750843759000},"page":"5634-5651","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Notoginsenoside\n                    <scp>R1<\/scp>\n                    , a Novel Natural\n                    <scp>PPAR\u03b3<\/scp>\n                    Agonist, Attenuates Cognitive Deficits in a Mouse Model of Diabetic Alzheimer's Disease Through Enhancing\n                    <scp>GLUT4<\/scp>\n                    \u2010Dependent Neuronal Glucose Uptake"],"prefix":"10.1002","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4479-0676","authenticated-orcid":false,"given":"Zongyang","family":"Li","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Shenzhen Key Laboratory of Neurosurgery, Shenzhen Institute of Translational Medicine, Shenzhen Second People's Hospital The First Affiliated Hospital of Shenzhen University  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8987-5986","authenticated-orcid":false,"given":"Yuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Shenzhen Key Laboratory of Neurosurgery, Shenzhen Institute of Translational Medicine, Shenzhen Second People's Hospital The First Affiliated Hospital of Shenzhen University  Shenzhen 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First Affiliated Hospital of Shenzhen University  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Shenzhen Key Laboratory of Neurosurgery, Shenzhen Institute of Translational Medicine, Shenzhen Second People's Hospital The First Affiliated Hospital of Shenzhen University  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Shenzhen Key Laboratory of Neurosurgery, Shenzhen Institute of Translational Medicine, Shenzhen Second People's Hospital The First Affiliated Hospital of Shenzhen University  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sixian","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Shenzhen Key Laboratory of Neurosurgery, Shenzhen Institute of 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