Author(s): Dioli, Chrysoula
Date: 2021
Persistent ID: https://hdl.handle.net/1822/75899
Origin: RepositóriUM - Universidade do Minho
Subject(s): Tau; chronic stress; glucocorticoid receptor; brain plasticity; neurons; microglia; stress crónico; receptor de glucocorticoides; plasticidade cerebral; neurónios; microglia
Chronic stress and high levels of the stress hormone, glucocorticoid (GC), are implicated in susceptibility to brain pathologies such as depression or Alzheimer’s disease (AD), as they promote neural plasticity damage and glial reactivity, which can lead to dendritic/synaptic loss, reduced neurogenesis, mood deficits, and impaired cognition. Growing clinical evidence supports a pathological link between depression and AD and shared neurobiological underpinnings with chronic stress being a potential link between them. Exposure of AD animal models to chronic stress triggers Tau pathology (e.g. Tau hyperphosphorylation and accumulation); the latter is causally related to neuronal malfunction and atrophy. Despite the well-known role of Tau in regulating cytoskeletal dynamics, the involvement of Tau in neurostructural remodeling and neuroplastic damage caused by chronic stress in the adult brain remains poorly explored. In the first objective of my thesis, we demonstrated the crucial role of Tau and its malfunction in stress-driven neurogenic, but not astrogliogenic or oligodendrogenic, damage in the cytogenic niches of the adult brain of wild-type animals (hippocampus and subventricular zone-olfactory bulb system) as mice lacking Tau were protected against stress-driven neurogenic suppression. Also, we showed that chronic stress impacts differentially the distinct phases of maturation of newborn immature neurons in the adult hippocampus. The second objective of my thesis focused on the cell-specific actions of the glucocorticoid receptor, GR, in stress-induced Tau pathology. To examine the role of GR specifically in neurons or microglia under stress conditions, we generated P301LTau mice in which GR gene is conditionally inactivated either in forebrain neurons or in microglia. Our findings show that GR was required in both cell types for chronic stress to induce cognitive deficits. Further analyses (which are ongoing) showed that neuronal GR is important in precipitating Tau neuropathology, and apical spine loss in CA1 hippocampal area. Microglial GR was found to affect microglial reactivity both in response to P301LTau as well as chronic stress-induced Tau pathology. Deletion of microglial GR results in spine loss whereas, it promotes spinogenesis under stress. However, it does not appear to impact Tau aggregation/accumulation. In conclusion, our data point to an important role of neuronal GR in mediating stress-driven Tau neuropathology and also identifies the essential role of microglial GR in stress-induced cognitive deficits. Given that the modern lifestyle increasingly exposes individuals to high stress loads, it is clear that understanding the mechanistic link(s) between chronic stress and AD pathogenesis may facilitate the treatment of AD and other related disorders.
