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

Abstract

See next page for additional authorsThis is an author-produced, peer-reviewed version of this article. © 2009, Elsevier. Licensed under the Creative Commons AttributionNonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/). The final, definitive version of this document can be found online at Neurobiology of Disease, doi: 10.1016Disease, doi: 10. /j.nbd.2010

Autophagy: for better or for worse

“…In this respect, Beclin-1 expression in human brain was found to decrease with age [203]. Moreover, caspase-mediated cleavage of Beclin-1 was observed in brain tissues of Alzheimer's patients [204].…”

Molecular Mechanism Underlying Aβ Immunotherapy: Implications for the Toxic Action of Aβ Oligomers

“…Beclin1 cleavage inactivates the autophagic function of Beclin1, whereas Beklin1-C acquires apoptosisinducing activity by translocating from the cytosol to the mitochondria, accelerating apoptosis probably via the enhancement of the release of cytochrome C [55][56][57]. Indeed, the caspase-induced cleavage of Beclin1 was observed in the AD brain [58]. In contrast, a new mouse model expressing only AβOs in neurons provides evidence of caspase-3 activation in the brain via lysosomal leakage and mitochondrial dysfunction [12].…”

“…As shown in Figure 1, sortilin forms a death signaling receptor with p75 NTR in response to AβOs, inducing p75 NTR -mediated apoptosis via Go, c-Jun N-terminal kinase (JNK), NADPH oxidase, and caspase-3-released caspases [51]. Recently, Sotthibundhu et al have NTR -sortilin death receptors are formed on the neuronal membrane [14], inducing p75 NTR -mediated apoptosis via Go, c-Jun N-terminal kinase 3 (JNK3), caspase-3-released caspases [51].The activated caspase-3 cleaves Beclin1, which attenuates the autophagy, whereas the resulting Beclin1-C causes mitochondria-mediated apoptosis [53][54][55][56][57][58]. Sortilin induces endocytosis of AβOs [14] into lysosomes [65], resulting in lysosomal leakage [12] and the subsequent mitochondrial apoptosis [12].…”

“…Sortilin induces endocytosis of AβOs [14] into lysosomes [65], resulting in lysosomal leakage [12] and the subsequent mitochondrial apoptosis [12]. In addition to the cleavage of Beclin1 [53][54][55][56][57][58], the resulting activated caspase-3 causes the cleavage of tau [61][62][63], followed by tau assembly [64,65] and phosphorylation [11,14,60]. Incomplete chaperone-mediated autophagy of tau [64] also induces the generation of amyloidogenic fragments that can self-assemble and phosphorylated by AβOs leaked from lysosomes.…”

Autophagy and neurodegeneration

“…Caspase-3, which may be activated in AD neurons, can also cleave beclin 1, resulting in impaired autophagosome formation (20). When crossed with beclin 1 haploinsufficient mice, mice overexpressing human APP exhibited autophagy disruption and enhanced pathology (18).…”