Rice bran oil rescues cognitive decline in D-galactose-induced aging mice by inhibiting Aβ accumulation and Tau hyperphosphorylation induced oxidative stress and neuroinflammation

Alzheimer's disease (AD) is a neurodegenerative disorder associated with brain aging, and the accumulation of β-amyloid (Aβ) and hyperphosphorylated Tau proteins are key pathological features. Currently, drugs for the treatment of AD are mainly single-targeted, but the complex pathogenesis of AD makes it difficult to achieve the desired results. Therefore, the development of multitargeted therapies is crucial for future interventions. Rice bran oil (RBO) has been recognized as an edible oil with several health benefits, but its effects on AD caused by brain aging remain underexplored. In this study, the effects of RBO on memory dysfunction in D-galactose (D-gal) mice and its molecular mechanisms were investigated via in vivo and in silico methods from the perspective of AD pathologies. Our results suggested that compounds in RBO could modulate the activities of Aβ precursor protein cleaving enzyme 1 (BACE1), mitogen-activated protein kinase 3 (MAPK3), matrix metalloproteinase 3 (MMP3), and intercellular adhesion molecule 1 (ICAM1), leading to inhibition of Aβ accumulation and Tau protein hyperphosphorylation. Moreover, RBO reduced Aβ-induced oxidative stress by inhibiting the activity of mouse double minute 2 homolog (MDM2) and cyclic adenosine monophosphate (cAMP) response element binding protein binding protein (CREBBP), and attenuated neuroinflammation by inhibiting the activity of nitric oxide synthase 2 (NOS2) and reducing Aβ accumulation and Tau protein hyperphosphorylation. Additionally, α-linolenic acid in RBO exhibited inhibitory effects on D-gal-induced apoptosis in PC12 cells through modulation of NOS2, MDM2, ICAM1, and phospho-extracellular signal-regulated kinase 1/2 (p-ERK1/2). Similarly, stigmastanol inhibited apoptosis in D-gal-induced PC12 cells through the regulation of NOS2. Thus, RBO can be considered as a potential functional food to attenuate AD owing to its multicomponent and multitarget effects.