Sex Hormone Depletion Augments Glucocorticoid Induction of Tau Hyperphosphorylation in Male Rat Brain

Steroid hormones secreted by the gonads (sex steroids) and adrenal glands (glucocorticoids, GC) are known to influence brain structure and function. While levels of sex steroids wane in late adulthood, corticosteroid levels tend to rise in many individuals due to age-related impairments in their feedback on central mechanisms regulating adrenal function. These fluctuations in sex and adrenal steroid secretion may be relevant to age-related neurodegenerative disorders such as Alzheimer's disease (AD) in which hyperphosphorylation of Tau protein is a key pathological event. We here report that both, long-term GC deprivation (by adrenalectomy) and exogenous GC administration with natural or synthetic glucocorticoid receptor ligands (corticosterone and dexamethasone, respectively) induce Tau hyperphosphorylation in the hippocampus and frontocortical regions at epitopes associated with disruption of cytoskeletal and synaptic function. Interestingly, we observed that the changes in Tau induced by manipulation of the GC milieu of male rats were exacerbated by testosterone depletion (by orchiectomy). While this finding supports previous suggestions of a neuroprotective role of male sex hormones, this is the first study to address interactions between adrenal and sex steroids on Tau hyperphosphorylation and accumulation that are known to endanger neuronal function and plasticity. These results are particularly important for understanding the mechanisms that can precipitate AD because, besides being modulated by age, GC are elevated by stress, a phenomenon now established as a trigger of deficits in neural plasticity and survival, cognitive behaviour and AD-like Tau pathology.