Ioannis Sotiropoulos - ICVS, University of Minho
Title: Tau therapeutics in stress-driven brain pathology: exploring the path from depression to Alzheimer’s disease
Abstract:
Synaptic malfunction is a key pathomechanism in both depressive and Alzheimer´s disease (AD) pathologies with chronic stress and stress hormones, glucocorticoids (GC), being a risk factor for both disorders. Accumulating evidence has suggested the continuum between depression, impaired cognition and AD raising stress, a well-known sculptor of brain plasticity, as potential connecting factor. As Tau protein and its hyperphosphorylation have been implicated in neuronal/synaptic malfunction in AD brain, we hereby assessed whether Tau plays a critical role in stress-driven depressive pathology and associated cognitive decline. For that purpose, we exposed Tau knock-out (Tau-KO) mice and their wild-type (WT) littermates in chronic unpredictable stress. Our recent findings demonstrate, for the first time, that stress and GC-driven neuronal deficits in wild-type mice are accompanied by synaptic missorting of Tau and enhanced Fyn/GluN2B-driven synaptic signaling assessed by both molecular (WB) and ultrastructural (TEM) analysis [1, 2]. In contrast, mice lacking Tau (Tau-KO) Tau-KO mice are resilient to chronic stress exhibiting no depressive-like behavior and cognitive impairments while, in contrary to WT, stressed Tau-KO also did not display neuronal/synaptic atrophy, reduction in synaptic plasticity and MRI-based neuronal activity [1]. Furthermore, our quantitative proteomic analysis of synaptosomal fractions, combined with TEM analysis, suggested a prominent role for mitochondria in the regulation of the effects of stress affecting their synaptic localization and function [3]. These findings identify Tau as an essential mediator in the orchestration of cellular cascades underlying dendritic and synaptic atrophy/loss in stress-evoked depressive pathology and associated cognitive deficits adding to our molecular understanding of how stress precipitates brain pathology.
Title: Tau therapeutics in stress-driven brain pathology: exploring the path from depression to Alzheimer’s disease
Abstract:
Synaptic malfunction is a key pathomechanism in both depressive and Alzheimer´s disease (AD) pathologies with chronic stress and stress hormones, glucocorticoids (GC), being a risk factor for both disorders. Accumulating evidence has suggested the continuum between depression, impaired cognition and AD raising stress, a well-known sculptor of brain plasticity, as potential connecting factor. As Tau protein and its hyperphosphorylation have been implicated in neuronal/synaptic malfunction in AD brain, we hereby assessed whether Tau plays a critical role in stress-driven depressive pathology and associated cognitive decline. For that purpose, we exposed Tau knock-out (Tau-KO) mice and their wild-type (WT) littermates in chronic unpredictable stress. Our recent findings demonstrate, for the first time, that stress and GC-driven neuronal deficits in wild-type mice are accompanied by synaptic missorting of Tau and enhanced Fyn/GluN2B-driven synaptic signaling assessed by both molecular (WB) and ultrastructural (TEM) analysis [1, 2]. In contrast, mice lacking Tau (Tau-KO) Tau-KO mice are resilient to chronic stress exhibiting no depressive-like behavior and cognitive impairments while, in contrary to WT, stressed Tau-KO also did not display neuronal/synaptic atrophy, reduction in synaptic plasticity and MRI-based neuronal activity [1]. Furthermore, our quantitative proteomic analysis of synaptosomal fractions, combined with TEM analysis, suggested a prominent role for mitochondria in the regulation of the effects of stress affecting their synaptic localization and function [3]. These findings identify Tau as an essential mediator in the orchestration of cellular cascades underlying dendritic and synaptic atrophy/loss in stress-evoked depressive pathology and associated cognitive deficits adding to our molecular understanding of how stress precipitates brain pathology.