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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


Chen, Qingfa; Ma, Hongling; Guo, Xuewen; Liu, Jia; Gui, Ting; Gai, Zhibo (2019). 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. Medical Science Monitor, 25:9335-9345.

Abstract

BACKGROUND: Alzheimer’s disease (AD), which results in cognitive deficits, usually occurs in older people and is mainly caused by amyloid beta (Aß) 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 AND 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 Aß. Co-immunoprecipitation was used to analyze the molecular partners involved in Aß-induced apoptosis.
RESULTS: We found that the mRNA and protein expression of FXR was enhanced in Ab-triggered neuronal apoptosis in differentiated SH-SY5Y cells and in mouse hippocampal neurons. Overexpression of FXR aggravated Aß-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 Aß-triggered neuronal apoptosis effect and prevented the reduction in CREB and BDNF.
CONCLUSIONS: These data suggest that FXR regulates Aß-induced neuronal apoptosis, which may be dependent on the CREB/BDNF signaling pathway in vitro.

Abstract

BACKGROUND: Alzheimer’s disease (AD), which results in cognitive deficits, usually occurs in older people and is mainly caused by amyloid beta (Aß) 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 AND 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 Aß. Co-immunoprecipitation was used to analyze the molecular partners involved in Aß-induced apoptosis.
RESULTS: We found that the mRNA and protein expression of FXR was enhanced in Ab-triggered neuronal apoptosis in differentiated SH-SY5Y cells and in mouse hippocampal neurons. Overexpression of FXR aggravated Aß-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 Aß-triggered neuronal apoptosis effect and prevented the reduction in CREB and BDNF.
CONCLUSIONS: These data suggest that FXR regulates Aß-induced neuronal apoptosis, which may be dependent on the CREB/BDNF signaling pathway in vitro.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Clinical Pharmacology and Toxicology
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > General Medicine
Uncontrolled Keywords:General Medicine
Language:English
Date:8 December 2019
Deposited On:14 Feb 2020 12:54
Last Modified:22 Jun 2024 01:42
Publisher:Medical Science International Publishing
ISSN:1234-1010
OA Status:Green
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.12659/msm.920065
PubMed ID:31812977