Efectos del estrés crónico sobre el envejecimientomecanismos implicados en el desarrollo de la enfermedad de Alzheimer

Resum

There is much interest in understanding the mechanisms responsible for interactions among stress, aging, memory and Alzheimer's disease (AD). Glucocorticoid secretion associated with stress may contribute to the variability of the aging process and to the development of neuropathologies. Maternal separation (MS) and chronic mild stress (CMS) were used to study the interactions between stress and aging. Aged MS rats showed an altered HPA axis reactivity and cognitive impairments. Levels of phosphorylated insulin receptor and markers of insulin downstream signalling pathways were significantly decreased in aged rats. There was a significant decrease in pERK2 and in the plasticity marker Arc in MS aged rats. It is interesting to note that there was a significant increase in the C99:C83 ratio, amyloid beta levels, and BACE1 levels the hippocampus of MS aged rats, suggesting that there was an increase in the amyloidogenic processing of APP. CMS aged mice showed both learning impairment in the novel object recognition test and insulin resistance detected by the HOMA index. Synaptophysin and beta-catenin were decreased whereas pJNK was increased in CMS aged mice, which also exhibited decreased hippocampal levels of pIRS, pAkt, pGSK3beta and pERK1/2 and increased levels of ptau. Moreover, alterations of HPA axis and insulin levels were observed in the CSF of AD patients. These results are integrated in a tentative mechanism through which aging interplay with stress to influence cognition as the basis of AD. The present results may provide the proof-of-concept for the use of glucocorticoid-/insulin-related drugs in the treatment of AD.