Notoginsenoside R1, a Novel Natural PPARγ Agonist, Attenuates Cognitive Deficits in a Mouse Model of Diabetic Alzheimer's Disease Through Enhancing GLUT4‐Dependent Neuronal Glucose Uptake

ABSTRACT Our previous studies demonstrated the potential of notoginsenoside R1 (NGR1), a primary bioactive compound from Panax notoginseng , in alleviating diabetic encephalopathy in db/db mice and mitigating amyloid‐β (Aβ)‐induced neuronal damage. This study aimed to investigate the positive effects of NGR1 against cognitive deficits in a diabetic Alzheimer's disease (AD) mouse model (APP/PS1x db/db mice). APP/PS1x db/db mice were intragastrically administrated with NGR1 (40 mg/kg/day) or co‐administrated with NGR1 and a selective PPARγ inhibitor GW9662 for 16 weeks. We identified NGR1 as a novel PPARγ agonist through molecular docking, surface plasmon resonance, and dual‐luciferase reporter assay. NGR1 treatment significantly promoted the membrane translocation of GLUT4 and enhanced 2‐deoxyglucose uptake in primary mouse hippocampal neurons. Furthermore, NGR1 treatment notably mitigated cognitive deficits in APP/PS1x db/db 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 Aβ burden, suppressed microglia‐induced neuroinflammation, and notably increased cerebral glucose uptake, as demonstrated by 18 F‐FDG PET scans. NGR1 treatment could upregulate PPARγ and GLUT4 expression and increase phosphorylation of Akt at Ser473 while decreasing phosphorylation of IRS‐1 at Ser616 in the hippocampus of APP/PS1x db/db mice. Crucially, the protective effects of NGR1 were abolished by co‐administration with GW9662. NGR1 demonstrated efficacy in enhancing neuronal glucose uptake through the activation of the PPARγ/Akt/GLUT4 signaling pathways in APP/PS1x db/db mice, positioning it as a promising candidate for diabetic AD treatment.