Depletion of Beclin-1 due to proteolytic cleavage by caspases in the Alzheimer's disease brain

NEUROBIOLOGY OF DISEASE

卷:43

Article

Rohn, Troy T.¹  Wirawan, Ellen^2,3  Brown, Raquel J.¹  Harris, Jordan R.¹  Masliah, Eliezer⁴  Vandenabeele, Peter^2,3 

[1] Boise State Univ, Dept Biol Sci, Boise, ID 83725 USA

[2] VIB, Dept Mol Biomed Res, Unit Mol Signaling & Cell Death, B-9052 Ghent, Belgium

[3] Univ Ghent, Dept Biomed Mol Biol, Unit Mol Signaling & Cell Death, B-9052 Ghent, Belgium

[4] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA

关键词: Beclin-1;    Alzheimer's disease;    Astrocytes;    Caspase;   

DOI  :  10.1016/j.nbd.2010.11.003

来源: Elsevier

【 摘 要 】

The Beclin-1 protein is essential for the initiation of autophagy, and recent studies suggest this function may be compromised in Alzheimer's disease (AD). In addition, in vitro studies have supported a loss of function of Beclin-1 due to proteolytic modification by caspases. In the present study, we examined whether caspase-cleavage of Beclin-1 occurs in the AD brain by designing a site-directed caspase-cleavage antibody based upon a known cleavage site within the protein at position D149. We confirmed that Beclin-1 is an excellent substrate for caspase-3 and demonstrates cleavage led to the formation of a 35-kDa C-terminal fragment labeled by our novel antibody following Western blot analysis. Application of this antibody termed Beclin-1 caspase-cleavage product antibody or BeclinCCP in frontal cortex tissue sections revealed strong immunolabeling within astrocytes that localized with plaque regions and along blood vessels in all AD cases examined. In addition, weaker, more variable BeclinCCP labeling was also observed within neurofibrillary tangles that colocalized with the early tau conformational marker. MC-1 as well as the late tangle marker, PHF-1. Collectively, these data support a depletion of Beclin-1 in AD following caspase-cleavage. This article is part of a Special Issue entitled Autophagy and protein degradation in neurological diseases. (C) 2010 Elsevier Inc. All rights reserved.

【 授权许可】

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