title: Insulin-activated Akt rescues Aβ oxidative stress-induced cell death by orchestrating molecular trafficking.
abstract: 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.
authors.affiliation: Istituto di Biomedicina ed Immunologia Molecolare Alberto Monroy, Consiglio Nazionale delle Ricerche, via Ugo La Malfa 153, Palermo, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Picone
authors.forename: Daniela
authors.initials: D
authors.lastname: Giacomazza
authors.forename: Valeria
authors.initials: V
authors.lastname: Vetri
authors.forename: Rita
authors.initials: R
authors.lastname: Carrotta
authors.forename: Valeria
authors.initials: V
authors.lastname: Militello
authors.forename: Pier L
authors.initials: PL
authors.lastname: San Biagio
authors.forename: Marta
authors.initials: M
authors.lastname: Di Carlo
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D015153:Blotting, Western; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006593:Hexokinase / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000633:toxicity*; D010766:Phosphorylation; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D011994:Recombinant Proteins / Q000633:toxicity; D015398:Signal Transduction; D013997:Time Factors; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; C494819:BAD protein, human; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007328:Insulin; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; C075222:amyloid beta-protein (1-42); D051025:bcl-Associated Death Protein; D006593:Hexokinase; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt