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 β-
amyloid (Aβ) 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 Aβ production by mechanisms involving reduction in levels of β-
amyloid precursor
protein (APP) and β-
secretase (BACE1), the
enzyme that initiates cleavage of APP to yield Aβ
peptides. Additionally, 27-OHC-induced tau phosphorylation, ROS generation, TNF-α activation, and
iron and
apoptosis-regulatory protein levels alteration were also markedly reduced by
siRNA to gadd153. These data suggest that ER stress-mediated gadd153 activation plays a central role in the triggering of AD pathological hallmarks that result from incubation of hippocampal slices with 27-OHC. Our results add important insights into cellular mechanisms that underlie the potential contribution of
cholesterol metabolism in AD pathology, and suggest that preventing gadd153 activation protects against AD related to
cholesterol oxidized products.