Berberine Improves Behavioral and Cognitive Deficits in a Mouse Model of Alzheimer's Disease via Regulation of β-Amyloid Production and Endoplasmic Reticulum Stress

Alzheimer's disease (AD) is a neurodegenerative disease characterized by beta-amyloid (A beta), neurofibrillary tangles, and neuronal cell death. Aggressive A beta accumulation accelerates senile plaque formation and perturbs endoplasmic reticulum (ER) function. A beta accumulation-induced changes stimulate the unfolded protein response (UPR), which can trigger neuronal apoptosis. Protein kinase RNA-like endoplasmic reticulum kinase (PERK), whose activation is stress-dependent, increases the phosphorylation of eukaryotic translation initiation factor-2 alpha (eIF2 alpha). eIF2 alpha promotes the synthesis of beta-site APP cleavage enzyme 1 (BACE1), which in turn facilitates A beta generation and subsequent neuronal apoptosis. In this study, we investigated whether berberine could improve cognitive deficits in the triple-transgenic mouse model of Alzheimer's disease (3 x Tg AD) mice. Our results revealed that berberine treatment may inhibit PERK/eIF2 alpha signaling-mediated BACE1 translation, thus reducing A beta production and resultant neuronal apoptosis. Further, berberine may have neuroprotective effects, via attenuation of ER stress and oxidative stress. In sum, our study demonstrates the therapeutic potential of berberine for treating AD.