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Functional Consequences of Stress : Impact of in vitro Stress Exposure on Tau Phosphorylation, Aggregation, and Axonal Transport

  • Author(s): Le, Michelle H.
  • et al.
Abstract

Stress is implicated as a contributing factor in Alzheimers Disease (AD). Individuals prone to psychological distress as a consequence of stress exposure are at three times greater risk of AD than age-matched controls. Hyperphosphorylation of tau is a key event leading to AD neurofibrillary tangles, which positively correlates with cognitive decline. Because tau is the primary stabilizing protein of microtubules (MTs), it is thought that tau phosphorylation (tau-P) and aggregation causes dissociation of tau on MTs, leading to MT destabilization and disruption in axonal transport. We have shown that restraint stress induces hippocampal tau-P in rodents, a process that involves corticotropin- releasing factor receptor type 1 (CRFR1), with repeated exposure showing increased hippocampal tau-P in insoluble aggregates. Although these data provide a potential link between chronic stress and AD tauopathy, the impact of stress-induced tau-P on neuronal function is still unclear. To test the hypothesis that stress-induced tau-P causes dissociation of tau from MTs and dysfunction in axonal transport, we developed a neuronal in vitro system to analyze how modulation of tau by stress hormones impact cell viability and axonal transport of cargoes. Mouse hippocampal neurons were exposed to stress-system intermediates : CRF, corticosterone (cort), or control for 0-24 hours. CRF and cort showed increased tau-P over the timecourse examined. We also observed activation of specific tau kinases. We examined characteristics of axonal transport of mitochondria and BDNF. Collectively, our results suggest that stress alters cellular processes and CRFR1 antagonism may be a useful therapeutic strategy for AD tauopathy and neuronal dysfunction

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