beta-amyloid induces neuronal apoptosis via a mechanism that involves the c-Jun N-terminal kinase pathway and the induction of Fas ligand

Elevated levels of beta -Amyloid (A beta) are present in the brains of indi viduals with either the sporadic or familial form of Alzheimer's disease (A D), and the deposition of A beta within the senile plaques that are a hallm ark of AD is thought to be a primary cause of the cognitive dysfunction tha t occurs in AD. Recent evidence suggests that A beta induces neuronal apopt osis in the brain and in primary neuronal cultures, and that this A beta -i nduced neuronal death may be responsible in part for the cognitive decline found in AD patients. In this study we have characterized one mechanism by which A beta induces neuronal death. We found that in cortical neurons expo sed to A beta, activated c-Jun N-terminal kinase (JNK) is required for the phosphorylation and activation of the c-Jun transcription factor, which in turn stimulates the transcription of several key target genes, including th e death inducer Fas ligand. The binding of Fas ligand to its receptor Fas t hen induces a cascade of events that lead to caspase activation and ultimat ely cell death. By analyzing the effects of mutations in each of the compon ents of the JNK-c-Jun-Fas ligand-Fas pathway, we demonstrate that this path way plays a critical role in mediating Ap-induced death of cultured neurons . These findings raise the possibility that the JNK pathway may also contri bute to A beta -dependent death in AD patients.