Neuroprotective Effect of Caffeic Acid Phenethyl Ester in A Mouse Model of Alzheimer's Disease Involves Nrf2/HO-1 Pathway

Alzheimer's disease (AD) is a progressive pathology, where dementia symptoms gradually worsen over a number of years. The hallmarks of AD, such as amyloid beta-peptide (A beta) in senile plaque and neurofibrillary tangles, are strongly intertwined with oxidative stress, which is considered one of the common effectors of the cascade of degenerative events. The endogenous nuclear factor erythroid 2-related factor 2 (Nrf2) is the master regulator of the antioxidant response and it is known as an indicator and regulator of oxidative stress. The present study aimed to determine the potential neuroprotective activity of caffeic acid phenethyl ester (CAPE), a poly phenolic compound abundant in honeybee, against the neurotoxicity of A beta(1-42) oligomers (A beta O) in mice. An intracerebroventricular (i.c.v.) injection of A beta O into the mouse brain triggered increased reactive oxygen species levels, neurodegeneration, neuroinflammation, and memory impairment. In contrast, the intraperitoneal administration of CAPE (10 mg/kg) after i.c.v. A beta O-injection counteracted oxidative stress accompanied by an induction of Nrf2 and heme oxygenase-1 via the modulation of glycogen synthase kinase 3 beta in the hippocampus of mice. Additionally, CAPE treatment decreased A beta O-induced neuronal apoptosis and neuroinflammation, and improved learning and memory, protecting mice against the decline in spatial cognition. Our findings demonstrate that CAPE could potentially be considered as a promising neuroprotective agent against progressive neurodegenerative diseases such as AD.