A beta 1-42 monomers or oligomers have different effects on autophagy and apoptosis

作者：Guglielmotto Michela; Monteleone Debora; Piras Antonio; Valsecchi Valeria; Tropiano Marta; Ariano Stefania; Fornaro Michele; Vercelli Alessandro; Puyal Julien; Arancio Ottavio; Tabaton Massimo; Tamagno Elena^*

来源：Autophagy, 2014, 10(10): 1827-1843.

DOI：10.4161/auto.30001

• Alzheimer disease
• apoptosis
• autophagy
• BCL2
• BECN1
• soluble beta-amyloid 42

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-beta (A beta) peptide accumulation in vacuoles and cell death. A beta, in turn, has been found to affect autophagy. Thus, A beta 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 A beta 1-42 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-BECN 1 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.

• 出版日期2014-10