PPAR-γ modulation restores the adiponectin-AMPK-AKT axis to attenuate metabolic stress-associated alzheimer's pathology.

Background Increasing evidence links metabolic dysregulation, insulin resistance, and endotoxin-induced inflammation to sporadic AD. A disruption of the PPARγ-adiponectin-AMPK-insulin pathway leads to neuroinflammation, Aβ buildup, tau hyperphosphorylation, and cognitive impairments. This study examined the neuroprotective effects of telmisartan and formononetin alone and in combination in metabolically primed AD-like rats. Methodology A two-hit model was employed to simulate metabolic endotoxemia-related sporadic Alzheimer's disease in male wistar rats. The model utilised chronic HFD feeding and systemic administration of LPS (250 µg/kg, i.p.). The animals received telmisartan, formonoetin, their combination, or a PPARγ inhibitor/ blocker. We evaluated metabolic parameters, cognitive performance, insulin resistance, inflammatory cytokines, adiponectin concentrations, cholinergic function, histopathology, and immunohistochemical markers of Aβ, tau, IRS-1, AMPK, and AKT signalling. Results The outcomes of HFD + LPS encompass weight gain, insulin resistance, inflammation, cholinergic dysfunction, neurotoxicity, elevated Aβ and tau pathology, and cognitive impairment. The therapy with telmisartan and formononetin enhanced these alterations in a dose-dependent manner, with the combination regimen demonstrating greater efficacy. The treatment reinstated adiponectin levels, enhanced AdipoR1-AMPK-AKT signalling, diminished pathogenic IRS-1 serine phosphorylation, reduced pro-inflammatory cytokines, maintained neuronal structure, and augmented recognition memory. The co-administration of PPARγ inhibitor/blocker abolished these protective effects, showing mediation reliance on PPARγ. Conclusion Telmisartan and formononetin have significant metabolic and neuroprotective advantages against AD generated by HFD and LPS through the activation of the PPARγ-adiponectin-AMPK-IRS-1-AKT signalling pathway. Targeting metabolic-inflammatory pathways using natural PPARγ modulators may aid in delaying or preventing sporadic AD associated with obesity, insulin resistance, and endotoxemia.