silencing gadd153chop gene expression protects against alzheimers disease-like pathology induced by 27-hydroxycholesterol in rabbit hippocampus基因表达沉默gadd153chop预防阿尔茨海默病病理27-hydroxycholesterol诱导的兔海马.pdfVIP

Silencing GADD153/CHOP Gene Expression Protects against Alzheimer’s Disease-Like Pathology Induced by 27-Hydroxycholesterol in Rabbit Hippocampus Jaya R. P. Prasanthi, Tyler Larson, Jared Schommer, Othman Ghribi* Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota, United States of America Abstract Endoplasmic reticulum (ER) stress is suggested to play a key role in the pathogenesis of neurodegenerative diseases including Alzheimer’s disease (AD). Sustained ER stress leads to activation of the growth arrest and leucine zipper transcription factor, DNA damage inducible gene 153 (gadd153; also called CHOP). Activated gadd153 can generate oxidative damage and reactive oxygen species (ROS), increase b-amyloid (Ab) levels, disturb iron homeostasis and induce inflammation as well as cell death, which are all pathological hallmarks of AD. Epidemiological and laboratory studies suggest that cholesterol dyshomeostasis contributes to the pathogenesis of AD. We have previously shown that the cholesterol oxidized metabolite 27-hydroxycholesterol (27-OHC) triggers AD-like pathology in organotypic slices. However, the extent to which gadd153 mediates 27-OHC effects has not been determined. We silenced gadd153 gene with siRNA and determined the effects of 27-OHC on AD hallmarks in organotypic slices from adult rabbit hippocampus. siRNA to gadd153 reduced 27-OHC-induced Ab production by mechanisms involving reduction in levels of b-amyloid precursor protein (APP) and b-secretase (BACE1), the enzyme that initiates cleavage of APP to yield Ab peptides. Additionally, 27-OHC-induced tau phosphorylation, ROS generation, TNF-a activation, and iron and apoptosis-regulatory protein levels alteration were also mar