Alzheimer’s disease (AD) is a brain disorder associated with a gradual weakening in neurocognitive functions, neuroinflammation,
and impaired signaling pathways. Resveratrol (RSV) has neuroprotective properties, but with low bioavailability, and
low solubility in vivo. Selenium (Se) is an essential micronutrient for brain function. Thus, this study aimed to evaluate the
role of formulated RSV-Se nanoparticles (RSV-SeNPs) on neurochemical and histopathological approaches associated with
the AD model in rats induced by Aluminumchloride (
AlCl3) at a dose of 100 mg/kg/day for 60 days. RSV-SeNPs supplementation
attenuates the impaired oxidative markers and mitochondrial dysfunction. The ameliorative effect of RSV-SeNPs
on cholinergic deficits was associated with clearance of amyloid β (Aβ). Furthermore, activation of phosphatidylinositol 3
kinase (PI3K) deactivates glycogen synthase kinase 3 beta (GSK-3β)-mediated tau hyperphosphorylation. Additionally, RSVSeNPs
downregulate signal transducer and activator of transcription (STAT3) expression as well as interleukin-1β (IL-1β)
levels, therefore alleviating neuroinflammation in AD. Moreover, RSV-SeNPs upregulate the expression of Sirtuin-1 (SIRT1)
and lower that of microRNA-134, consequently increasing neurite outgrowth. Eventually, the obtained results showed that
nano-formulation of resveratrol with selenium maximized the therapeutic potential of RSV against Alzheimer’s disease not
only by their antioxidant but also by anti-inflammatory effect improving the neurocognitive function and modulating the
signaling pathways.