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The Journal of Neuroscience, October 1, 2001, 21(19):7551-7560

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

Yoshiyuki Morishima¹, Yukiko Gotoh¹, Janine Zieg¹, Tamera Barrett², Hiromichi Takano³, Richard Flavell⁴, Roger J. Davis², Yasufumi Shirasaki³, and Michael E. Greenberg¹

¹ Division of Neuroscience, Children's Hospital, and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, ² Howard Hughes Medical Institute, Program in Molecular Medicine, Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, ³ New Products Research Laboratories III, Daiichi Pharmaceutical Co., Ltd., Tokyo 134-8636, Japan, and ⁴ Howard Hughes Medical Institute, Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510

Elevated levels of -Amyloid (A) are present in the brains of individuals with either the sporadic or familial form of Alzheimer's disease (AD), and the deposition of A 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 A induces neuronal apoptosis in the brain and in primary neuronal cultures, and that this A-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 A induces neuronal death. We found that in cortical neurons exposed to A, 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 A-induced death of cultured neurons. These findings raise the possibility that the JNK pathway may also contribute to A-dependent death in AD patients.

Key words: Alzheimer's disease; -amyloid; c-Jun N-terminal kinase; JNK; c-Jun; Fas; Fas ligand; apoptosis; neuronal cell death

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21197551-10$05.00/0

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