PT  - JOURNAL ARTICLE
AU  - Yao, Mingzhong
AU  - Nguyen, Thuy-Vi V.
AU  - Pike, Christian J.
TI  - β-Amyloid-Induced Neuronal Apoptosis Involves c-Jun N-Terminal Kinase-Dependent Downregulation of Bcl-w
AID  - 10.1523/JNEUROSCI.4736-04.2005
DP  - 2005 Feb 02
TA  - The Journal of Neuroscience
PG  - 1149--1158
VI  - 25
IP  - 5
4099  - http://www.jneurosci.org/content/25/5/1149.short
4100  - http://www.jneurosci.org/content/25/5/1149.full
SO  - J. Neurosci.2005 Feb 02; 25
AB  - β-Amyloid protein (Aβ) has been implicated as a key molecule in the neurodegenerative cascades of Alzheimer's disease (AD). Aβ directly induces neuronal apoptosis, suggesting an important role of Aβ neurotoxicity in AD neurodegeneration. However, the mechanism(s) of Aβ-induced neuronal apoptosis remain incompletely defined. In this study, we report that Aβ-induced neuronal death is preceded by selective alterations in expression of the Bcl-2 family of apoptosis-related genes. Specifically, we observe that Aβ significantly reduces expression of antiapoptotic Bcl-w and Bcl-xL, mildly affects expression of bim, Bcl-2, and bax, but does not alter expression of bak, bad, bik, bid, or BNIP3.Aβ-induced downregulation of Bcl-w appears to contribute to the mechanism of apoptosis, because Aβ-induced neuronal death was significantly increased by Bcl-w suppression but significantly reduced by Bcl-w overexpression. Downstream of Bcl-w, Aβ-induced neuronal apoptosis is characterized by mitochondrial release of second mitochondrion-derived activator of caspase (Smac), an important precursor event to cell death. We observed that Smac release was potentiated by suppression of Bcl-w and reduced by overexpression of Bcl-w. Next, we investigated the upstream mediator of Aβ-induced Bcl-w downregulation and Smac release. We observed that Aβ rapidly activates c-Jun N-terminal kinase (JNK). Pharmacological inhibition of JNK effectively inhibited all measures of Aβ apoptosis: Bcl-w downregulation, Smac release, and neuronal death. Together, these results suggest that the mechanism of Aβ-induced neuronal apoptosis sequentially involves JNK activation, Bcl-w downregulation, and release of mitochondrial Smac, followed by cell death. Complete elucidation of the mechanism of Aβ-induced apoptosis promises to accelerate development of neuroprotective interventions for the treatment of AD.