Farnesoid X Receptor (FXR) Aggravates Amyloid-β-Triggered Apoptosis by Modulating the cAMP-Response Element-Binding Protein (CREB)/Brain-Derived Neurotrophic Factor (BDNF) Pathway In Vitro

Background: Alzheimer's disease (AD), which results in cognitive deficits, usually occurs in older people and is mainly caused by amyloid beta (A beta) deposits and neurofibrillary tangles. The bile acid receptor, farnesoid X receptor (FXR), has been extensively studied in cardiovascular diseases and digestive diseases. However, the role of FXR in AD is not yet understood. The purpose of the present study was to investigate the mechanism of FXR function in AD. Material/Methods: Lentivirus infection, flow cytometry, real-time PCR, and western blotting were used to detect the gain or loss of FXR in cell apoptosis induced by A beta. Co-immunoprecipitation was used to analyze the molecular partners involved in A beta-induced apoptosis. Results: We found that the mRNA and protein expression of FXR was enhanced in A beta-triggered neuronal apoptosis in differentiated SH-SY5Y cells and in mouse hippocampal neurons. Overexpression of FXR aggravated A beta-triggered neuronal apoptosis in differentiated SH-SY5Y cells, and this effect was further increased by treatment with the FXR agonist 6ECDCA. Molecular mechanism analysis by co-immunoprecipitation and immunoblotting revealed that FXR interacted with the cAMP-response element-binding protein (CREB), leading to decreased CREB and brain-derived neurotrophic factor (BDNF) protein levels. Low expression of FXR mostly reversed the A beta-triggered neuronal apoptosis effect and prevented the reduction in CREB and BDNF. Conclusions: These data suggest that FXR regulates A beta-induced neuronal apoptosis, which may be dependent on the CREB/BDNF signaling pathway in vitro.