β-Amyloid Induces Neuronal Apoptosis Via a Mechanism that Involves the c-Jun N-Terminal Kinase Pathway and the Induction of Fas Ligand

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Abstract
Elevated levels of β-Amyloid (Aβ) are present in the brains of individuals with either the sporadic or familial form of Alzheimer9s 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, and that this Aβ-induced 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 Aβ induces neuronal death. We found that in cortical neurons exposed to Aβ, 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 the death inducer Fas ligand. The binding of Fas ligand to its receptor Fas then induces a cascade of events that lead to caspase activation and ultimately cell death. By analyzing the effects of mutations in each of the components of the JNK–c-Jun–Fas ligand–Fas pathway, we demonstrate that this pathway plays a critical role in mediating Aβ-induced death of cultured neurons. These findings raise the possibility that the JNK pathway may also contribute to Aβ-dependent death in AD patients.