In AD and possibly other forms

In AD, and possibly other forms of dementia, it has been suggested that tau mislocalization to dendritic spines anticipates neurodegeneration [48]. Accumulation of hyperphosphorylated tau in dendritic spies would cause a derangement of synaptic function, thereby impairing excitatory synaptic transmission [49], [50], [51]. In an elegant study, Ittner and coworkers have demonstrated that postsynaptically localized tyrosine kinase Fyn acts as a target for the “axonal” protein tau [49]. By phosphorylating the GluN2B subunit of NMDA receptors at Y1472, Fyn stabilizes extrasynaptic NMDA receptors on the cell surface, thereby enhancing NMDA receptor activity [52]. This biochemical scenario laid a groundwork for additional studies on the relationship between stress and AD. Lopes and colleagues [53] found that chronic exposure to CUS in wild-type mice caused behavioral disturbances, synaptic tau missorting, and enhanced levels of Fyn in hippocampal postsynaptic densities. None of these effects was observed in mice with genetic Dexmedetomidine HCl of tau protein. Of note, tau protein knockout mice did not show changes in plasma corticosterone levels in response to CUS or acute restraint stress. The Authors concluded that tau has an essential role linking chronic stress to synaptic pathology associated with AD.
Early life events, glucocorticoids and vulnerability to Alzheimer’s Disease Early life experiences can shape the behavioral and biochemical phenotype and affect the HPA response to stress in the adult life [54]. In APP-V717I x Tau-T301P (biAT) bigenic mice, Lesuis and colleagues have recently investigated the effects of early life stress (ELS) or neonatal handling (NH) from postnatal day 2 to day 9, on AD outcome [55]. At the age of 4 months, an increase in hippocampal Aß levels was observed in biAT mice subjected to ELS, while a reduction of Aß levels was found in the NH group. Life expectancy, which is known to be short in this TG line [56], was affected by postnatal manipulation. Postnatal handling prolonged survival rate and, on the contrary, ELS reduced the lifespan. As a possible mechanism explaining the dichotomy observed in adult biAT mice, the Authors hypothesized a different degree of HPA axis activation (e.g., “high” in ELS, “low” in NH) induced by postnatal manipulation. While this suggestion has a solid base on the pertinent literature [57], [58], [59], a certain degree of maternal separation, which was intrinsic to the protocols employed in the study, might have critically influenced the regulation of the HPA axis. Accordingly, Michael Meaney and his colleagues have demonstrated that high levels of maternal care (licking/grooming and arched-back nursing), which might have occurred in the NH group, are associated with decreased DNA methylation of the glucocorticoid receptor gene, increased density of glucocorticoid receptor expression, greater feedback inhibition of the HPA axis and resilient stress responses in adulthood [see 60 for a review].
Conclusions In 1998 Bruce S. McEwen published a review article entitled “Protective and damaging effects of stress mediators” presented as part of the Seminars in Medicine of the Beth Israel Deaconess Medical Center [20]. In the general discussion which followed his presentation, Prof. McEwen was asked whether a correlation between lifelong stress and Alzheimer’s disease existed. Nearly 20 years have passed since then, and, as outlined above, clear evidence has been gained from preclinical studies indicating that glucocorticoids and/or CRH levels may shape the risk to develop AD. However, while it is advisable to reduce the burden of stress in AD patients, particularly in the early phases of the disease, it is hard to believed that specific anti-stress or anti-glucocorticoid/CRH treatments might be therapeutically helpful in AD, given the marked variability of individual resilience to stress. We wish to conclude with an Hans Selye’s citation of 1973 “Complete freedom from stress is death. Contrary to public opinion, we must not and indeed cannot avoid stress, but we can meet it efficiently and enjoy it by learning more about its mechanism and adjusting our philosophy of life accordingly” [61].