TY - JOUR
T1 - Insulin activated Akt rescues Aβ oxidative stress-induced cell death by orchestrating molecular trafficking.
AU - Vetri, Valeria
AU - Militello, Valeria
AU - Picone, Pasquale
AU - Carrotta, Rita
AU - San Biagio, Pier Luigi
AU - Giacomazza, Daniela
AU - Di Carlo, Marta
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
KW - Abeta peptide
KW - Akt
KW - Insulin
KW - cell death
KW - Abeta peptide
KW - Akt
KW - Insulin
KW - cell death
UR - http://hdl.handle.net/10447/62603
UR - http://onlinelibrary.wiley.com/doi/10.1111/j.1474-9726.2011.00724.x/full
M3 - Article
VL - 10
SP - 832
EP - 843
JO - Aging Cell
JF - Aging Cell
SN - 1474-9718
ER -