title: Depletion of Beclin-1 due to proteolytic cleavage by caspases in the Alzheimer's disease brain.
abstract: 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."
authors.affiliation: Department of Biological Sciences, Science/Nursing Building, Room 228, Boise State University, Boise, ID 83725, USA. trohn@boisestate.edu
authors.forename: Troy T
authors.initials: TT
authors.lastname: Rohn
authors.forename: Ellen
authors.initials: E
authors.lastname: Wirawan
authors.forename: Raquel J
authors.initials: RJ
authors.lastname: Brown
authors.forename: Jordan R
authors.initials: JR
authors.lastname: Harris
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenabeele
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D001253:Astrocytes / Q000473:pathology; D001343:Autophagy / Q000235:genetics; D000071186:Beclin-1; D001921:Brain / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D008875:Middle Aged; D059748:Proteolysis; D013379:Substrate Specificity / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; C505407:CASP3 protein, human; D053148:Caspase 3