Involvement of endoplasmic stress responses in Alzheimer disease

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Elevated levels of β-amyloid (Aβ) are present in the brains of individuals with either the sporadic or familial from of Alzheimer disease (AD), and the deposition of Aβ within the senile plaques that are a hallmark of AD is thought to be a primary cause of the cognitive dysfunction that occurs in AD. Recent evidence suggests that Aβ induces neuronal apoptosis in the brain and in primary neuronal cultures. It is also reported that responses for endoplasmic reticulum (ER) stress are involved in some neurodegenerative disorder including AD. In this study, we characterized a mechanism by which Aβ induces neuronal death. We found that in neurons exposed to A β, ER stress responses are activated, namely a phosphorylation of eIF2α and an induction, of GRP 78. It was also shown that the stress responses in ER by Aβ induces an activation of caspase 12 in mice or caspase 4 in human. Knock-down studies with dsRNA for caspase 12 or caspase 4 showed that apoptosis in neurons exposed to Aβ is mainly caused by the caspase related to ER. These findings raise the possibility that the ER stress pathway may contribute to Aβ -dependent death in AD patients.