Insulin protect by Abeta oxidative stress-induced cell death via activated Akt

Alzheimer's disease (AD) is a neurodegenerative disorder that currently affects nearly 2% of the population in industrialized countries and the risk of AD dramatically increases in individuals beyond the age of 65-70. AD patients lose their memory and cognitive abilities, and even their personalities may change dramatically. Insulin resistance, that is the reduced ability of insulin to stimulate glucose utilization, is a syndrome associated with Type II diabetes, hypertension, and obesity It is caused by impairment of the peripheral insulin receptor (IR), playing a pivotal role in regulation of peripheral glucose metabolism and energy homeostasis. Insulin receptors are also present in the brain and are involved in synaptic activities required for learning and memory. Recently, it has been suggested tha AD and diabetes may be related. Here we demonstrate that insulin signaling protects LAN5 cells by amyloid-?42 (A?) induced toxicity. A? affects both activation of insulin receptors (IRs) and the levels of phospho-Akt, a critical signaling molecule in this pathway. In contrast, oxidative stress induced by A? can be antagonized by active Akt that, in turn, inhibits Foxo3a, a pro-apoptotic transcription factor activated by ROS generation. Further, this data were confirmed by semi-quantitative PCR analysis in which modulation of Foxo3a, FasL, Bim, p27 expression was observed. Insulin cascade protects against mitochondrial damage caused by A? 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 of HK-II levels and by blocking apoptosis through phosphorylation of Bad, coming from cytoplasm after A? stimulus. Together these results indicate that the Akt survival signal antagonizes the A? cell death process by balancing the presence and modifications of common molecules in specific cellular environments.