Tags

Type your tag names separated by a space and hit enter

Beta-amyloid-induced neuronal apoptosis involves c-Jun N-terminal kinase-dependent downregulation of Bcl-w.
J Neurosci 2005; 25(5):1149-58JN

Abstract

beta-Amyloid protein (Abeta) has been implicated as a key molecule in the neurodegenerative cascades of Alzheimer's disease (AD). Abeta directly induces neuronal apoptosis, suggesting an important role of Abeta neurotoxicity in AD neurodegeneration. However, the mechanism(s) of Abeta-induced neuronal apoptosis remain incompletely defined. In this study, we report that Abeta-induced neuronal death is preceded by selective alterations in expression of the Bcl-2 family of apoptosis-related genes. Specifically, we observe that Abeta significantly reduces expression of antiapoptotic Bcl-w and Bcl-x(L), mildly affects expression of bim, Bcl-2, and bax, but does not alter expression of bak, bad, bik, bid, or BNIP3.Abeta-induced downregulation of Bcl-w appears to contribute to the mechanism of apoptosis, because Abeta-induced neuronal death was significantly increased by Bcl-w suppression but significantly reduced by Bcl-w overexpression. Downstream of Bcl-w, Abeta-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 Abeta-induced Bcl-w downregulation and Smac release. We observed that Abeta rapidly activates c-Jun N-terminal kinase (JNK). Pharmacological inhibition of JNK effectively inhibited all measures of Abeta apoptosis: Bcl-w downregulation, Smac release, and neuronal death. Together, these results suggest that the mechanism of Abeta-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 Abeta-induced apoptosis promises to accelerate development of neuroprotective interventions for the treatment of AD.

Authors+Show Affiliations

Andrus Gerontology Center, University of Southern California, Los Angeles, California 90089-0191, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15689551

Citation

Yao, Mingzhong, et al. "Beta-amyloid-induced Neuronal Apoptosis Involves c-Jun N-terminal Kinase-dependent Downregulation of Bcl-w." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 25, no. 5, 2005, pp. 1149-58.
Yao M, Nguyen TV, Pike CJ. Beta-amyloid-induced neuronal apoptosis involves c-Jun N-terminal kinase-dependent downregulation of Bcl-w. J Neurosci. 2005;25(5):1149-58.
Yao, M., Nguyen, T. V., & Pike, C. J. (2005). Beta-amyloid-induced neuronal apoptosis involves c-Jun N-terminal kinase-dependent downregulation of Bcl-w. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 25(5), pp. 1149-58.
Yao M, Nguyen TV, Pike CJ. Beta-amyloid-induced Neuronal Apoptosis Involves c-Jun N-terminal Kinase-dependent Downregulation of Bcl-w. J Neurosci. 2005 Feb 2;25(5):1149-58. PubMed PMID: 15689551.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Beta-amyloid-induced neuronal apoptosis involves c-Jun N-terminal kinase-dependent downregulation of Bcl-w. AU - Yao,Mingzhong, AU - Nguyen,Thuy-Vi V, AU - Pike,Christian J, PY - 2005/2/4/pubmed PY - 2005/9/15/medline PY - 2005/2/4/entrez SP - 1149 EP - 58 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J. Neurosci. VL - 25 IS - 5 N2 - beta-Amyloid protein (Abeta) has been implicated as a key molecule in the neurodegenerative cascades of Alzheimer's disease (AD). Abeta directly induces neuronal apoptosis, suggesting an important role of Abeta neurotoxicity in AD neurodegeneration. However, the mechanism(s) of Abeta-induced neuronal apoptosis remain incompletely defined. In this study, we report that Abeta-induced neuronal death is preceded by selective alterations in expression of the Bcl-2 family of apoptosis-related genes. Specifically, we observe that Abeta significantly reduces expression of antiapoptotic Bcl-w and Bcl-x(L), mildly affects expression of bim, Bcl-2, and bax, but does not alter expression of bak, bad, bik, bid, or BNIP3.Abeta-induced downregulation of Bcl-w appears to contribute to the mechanism of apoptosis, because Abeta-induced neuronal death was significantly increased by Bcl-w suppression but significantly reduced by Bcl-w overexpression. Downstream of Bcl-w, Abeta-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 Abeta-induced Bcl-w downregulation and Smac release. We observed that Abeta rapidly activates c-Jun N-terminal kinase (JNK). Pharmacological inhibition of JNK effectively inhibited all measures of Abeta apoptosis: Bcl-w downregulation, Smac release, and neuronal death. Together, these results suggest that the mechanism of Abeta-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 Abeta-induced apoptosis promises to accelerate development of neuroprotective interventions for the treatment of AD. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/15689551/Beta_amyloid_induced_neuronal_apoptosis_involves_c_Jun_N_terminal_kinase_dependent_downregulation_of_Bcl_w_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=15689551 DB - PRIME DP - Unbound Medicine ER -