Insulin‐activated Akt rescues Aβ oxidative stress‐induced cell death by orchestrating molecular trafficking

Aging Cell

Pasquale Picone¹  Daniela Giacomazza³  Valeria Vetri²  Rita Carrotta³  Valeria Militello²  Pier L. San Biagio³ 

[1] Istituto di Biomedicina ed Immunologia Molecolare (IBIM) “Alberto Monroy”, CNR, via Ugo La Malfa 153, 90146 Palermo, Italy;Dipartimento Scienze Fisiche ed Astronomiche (DSFA) Università di Palermo via Archirafi 36, 90123 Palermo, Italy;Istituto di BioFisica (IBF) CNR, via Ugo La Malfa 153, 90146 Palermo, Italy

关键词: amyloid‐beta;    insulin;    Akt;    apoptosis;    cell survival;    mitochondrion;   

DOI  :  10.1111/j.1474-9726.2011.00724.x

来源: Wiley

【 摘 要 】

Summary

Increasing evidence indicates that Alzheimer’s disease, one of the most diffused aging pathologies, and diabetes may be related. Here, we demonstrate that insulin signalling protects LAN5 cells by amyloid-β42 (Aβ)-induced toxicity. Aβ affects both activation of insulin receptors and the levels of phospho-Akt, a critical signalling molecule in this pathway. In contrast, oxidative stress induced by Aβ can be antagonized by active Akt that, in turn, inhibits Foxo3a, a pro-apoptotic transcription factor activated by reactive oxygen species generation. Insulin cascade protects against mitochondrial damage caused by Aβ treatment, restoring the mitochondrial membrane potential. Moreover, we show that the recovery of the organelle integrity recruits active Akt translocation to the mitochondrion. Here, it plays a role both by maintaining unimpaired the permeability transition pore through increase in HK-II levels and by blocking apoptosis through phosphorylation of Bad, coming from cytoplasm after Aβ stimulus. Together, these results indicate that the Akt survival signal antagonizes the Aβ cell death process by balancing the presence and modifications of common molecules in specific cellular environments.

【 授权许可】

Unknown   
© 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland