Analysis of underlying mechanism to develop Alzheimer's disease

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Gamma-secretase produces amyloid-beta (Ab) in the brain from Ab precursor protein, which is critical for tha pathogenesis of Alzheimer's disease (AD). The endoplasmic reticulum (ER) stress causes unfolded proteins, which are processed by unfolded protein response (UPR). Pathogenesis of obesity and diabetes, which are risk factors for AD, is related to ER stress. However, whether ER stress is engaged in the development of AD remains obscure. In this research, I showed that ER stress activated gamma-secretase, leading to augmentation of Ab through induction of activating transcription factor 4 (ATF4). Ab secretion was repressed in vitro by quercetin, which induced the growth arrest and DNA damaged-inducible gene (GADD)34. In addition, we found that phosphorylated eIF2alpha and ATF4 were increased in the brain of AD model mice APP23. These results suggest that ER stress signaling may be disturbed in the brain of AD.