Lupeol, a Plant-Derived Triterpenoid, Protects Mice Brains against Aβ-Induced Oxidative Stress and Neurodegeneration

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that represents 60-70% of all dementia cases. AD is characterized by the formation and accumulation of amyloid-beta (A beta) plaques, neurofibrillary tangles, and neuronal cell loss. Further accumulation of A beta in the brain induces oxidative stress, neuroinflammation, and synaptic and memory dysfunction. In this study, we investigated the antioxidant and neuroprotective effects of the natural triterpenoid lupeol in the A beta(1-42) mouse model of AD. An Intracerebroventricular injection (i.c.v.) of A beta (3 mu L/5 min/mouse) into the brain of a mouse increased the reactive oxygen species (ROS) levels, neuroinflammation, and memory and cognitive dysfunction. The oral administration of lupeol at a dose of 50 mg/kg for two weeks significantly decreased the oxidative stress, neuroinflammation, and memory impairments. Lupeol decreased the oxidative stress via the activation of nuclear factor erythroid 2-related factor-2 (Nrf-2) and heme oxygenase-1 (HO-1) in the brain of adult mice. Moreover, lupeol treatment prevented neuroinflammation by suppressing activated glial cells and inflammatory mediators. Additionally, lupeol treatment significantly decreased the accumulation of A beta and beta-secretase-1 (BACE-1) expression and enhanced the memory and cognitive function in the A beta-mouse model of AD. To the best of our knowledge, this is the first study to investigate the anti-oxidative and neuroprotective effects of lupeol against A beta(1-42)-induced neurotoxicity. Our findings suggest that lupeol could serve as a novel, promising, and accessible neuroprotective agent against progressive neurodegenerative diseases such as AD.