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

Stress exposure or increased levels of corticotropin-releasing factor (CRF) induce hippocampal tau phosphorylation (tau-P) in rodent models, a process that is dependent on the type-1 CRF receptor (CRFR1). Although these preclinical studies on stress-induced tau-P provide mechanistic insight for epidemiological work that identifies stress as a risk factor for Alzheimer's disease (AD), the actual impact of stress-induced tau-P on neuronal function remains unclear. To determine the functional consequences of stress-induced tau-P, we developed a novel mouse neuronal cell culture system to explore the impact of acute (0.5hr) and chronic (2hr) CRF treatment on tau-P and integral cell processes such as axon transport. Consistent with in vivo reports, we found that chronic CRF treatment increased tau-P levels and caused globular accumulations of phosphorylated tau in dendritic and axonal processes. Furthermore, while both acute and chronic CRF treatment led to significant reduction in CREB activation and axon transport of brain-derived neurotrophic factor (BDNF), this was not the case with mitochondrial transport. Acute CRF treatment caused increased mitochondrial velocity and distance traveled in neurons, while chronic CRF treatment modestly decreased mitochondrial velocity and greatly increased distance traveled. These results suggest that transport of cellular energetics may take priority over growth factors during stress. Tau-P was required for these changes, as co-treatment of CRF with a GSK kinase inhibitor prevented CRF-induced tau-P and all axon transport changes. Collectively, our results provide mechanistic insight into the consequences of stress peptide-induced tau-P and provide an explanation for how chronic stress via CRF may lead to neuronal vulnerability in AD.