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Autophagy. 2014 Oct 1;10(10):1827-43. doi: 10.4161/auto.30001. Epub 2014 Aug 12.

Aβ1-42 monomers or oligomers have different effects on autophagy and apoptosis.

Author information

1
Department of Neuroscience; University of Torino; Torino, Italy; Neuroscience Institute of Cavalieri Ottolenghi Foundation (NICO); University of Torino; Torino, Italy.
2
Department of Clinical and Biological Sciences; University of Torino; Torino, Italy; Neuroscience Institute of Cavalieri Ottolenghi Foundation (NICO); University of Torino; Torino, Italy.
3
Scienza della Formazione; University of Catania; Italy.
4
Department of Fundamental Neurosciences; Faculty of Biology and Medicine; University of Lausanne; Lausanne, Switzerland; Clinic of Neonatology; Department of Pediatrics and Pediatric Surgery; Lausanne University Hospital and University of Lausanne; Lausanne, Switzerland.
5
Department of Pathology and Cell Biology; Taub Institute for Research on Alzheimer's Disease and the Aging Brain; Columbia University; New York, NY USA.
6
Department of Internal Medicine; Unit of Geriatric Medicine; University of Genoa; Genoa, Italy.

Abstract

The role of autophagy and its relationship with apoptosis in Alzheimer disease (AD) pathogenesis is poorly understood. Disruption of autophagy leads to buildup of incompletely digested substrates, amyloid-β (Aβ) peptide accumulation in vacuoles and cell death. Aβ, in turn, has been found to affect autophagy. Thus, Aβ might be part of a loop in which it is both the substrate of altered autophagy and its cause. Given the relevance of different soluble forms of Aβ1-42 in AD, we have investigated whether monomers and oligomers of the peptide have a differential role in causing altered autophagy and cell death. Using differentiated SK-N-BE neuroblastoma cells, we found that monomers hamper the formation of the autophagic BCL2-BECN1/Beclin 1 complex and activate the MAPK8/JNK1-MAPK9/JNK2 pathway phosphorylating BCL2. Monomers also inhibit apoptosis and allow autophagy with intracellular accumulation of autophagosomes and elevation of levels of BECN1 and LC3-II, resulting in an inhibition of substrate degradation due to an inhibitory action on lysosomal activity. Oligomers, in turn, favor the formation of the BCL2-BECN1 complex favoring apoptosis. In addition, they cause a less profound increase in BECN1 and LC3-II levels than monomers without affecting the autophagic flux. Thus, data presented in this work show a link for autophagy and apoptosis with monomers and oligomers, respectively. These studies are likely to help the design of novel disease modifying therapies.

KEYWORDS:

Alzheimer disease; BCL2; BECN1; apoptosis; autophagy; soluble β-amyloid 42

PMID:
25136804
PMCID:
PMC4198366
DOI:
10.4161/auto.30001
[Indexed for MEDLINE]
Free PMC Article
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