Molecular mechanism of endoplasmic reticulum stress and Alzheimer disease

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Our previous reports showed that endoplasmic reticulum (ER) stress response was down-regulated in presenilin-1 mutant cells. Following the amyloid cascade hypothesis, we developed an interest in investigating the effects of ER stress on amyloid-β peptide (Aβ) generation. In the present study, we showed that treatment with an ER stressor resulted in the reduction of Aβ 40 and Aβ 42 generation. Immunocytochemical study and immunoblotting of subfractions showed that ER stress caused dislocation of amyloid precursor protein (APP) from late compartments to early compartments during the secretory pathway, and decreased levels of released Aβ by β and γ cutting despite no reduction of its secretase activities. Co-immunoprecipitation study showed that ER stress response facilitated binding of BiP/GRP78 to APP to be retained in early compartments, such as ER. In dominant-negative cells for ER stress, the reduction system of Aβ may deteriorate to cause relative accumulation of Aβ. These findings suggest that induction of BiP/GRP78 by ER stress may be one regulatory mechanism for Aβ generation.