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Exposure and/or sensitivity to stress have been implicated as conferring risk for development of Alzheimer's disease (AD). Although the basis for such a link remains unclear, we previously reported differential involvement of corticotropin-releasing factor receptor (CRFR) 1 and 2 in acute stress-induced tau phosphorylation (tau-P) and solubility in the hippocampus. Here we examined the role of CRFRs in tau-P induced by repeated stress and the structural manifestations of altered tau solubility. Robust tau-P responses were seen in WT and CRFR2 null mice exposed to repeated stress, which were sustained at even 24 h after the final stress exposure. A portion of phosphorylated tau in these mice was sequestered in detergent-soluble cellular fractions. In contrast, CRFR1 and CRFR double-KO mice did not exhibit repeated stress-induced alterations in tau-P or solubility. Similarly, treatment with CRFR1 antagonist attenuated repeated stress-induced tau-P. Using histochemical approaches in a transgenic CRFR1 reporter mouse line, we found substantial overlap between hippocampal CRFR1 expression and cells positive for phosphorylated tau after exposure to repeated stress. Ultrastructural analysis of negatively stained extracts from WT and CRFR2 null mice identified globular aggregates that displayed positive immunogold labeling for tau-P, as well as conformational changes in tau (MC1) seen in early AD. Given that repeated stress exposure results in chronic increases in hippocampal tau-P and its sequestration in an insoluble (and potentially prepathogenic) form, our data may define a link between stress and an AD-related pathogenic mechanism.

Corticotropin-releasing factor receptor-dependent effects of repeated stress on tau phosphorylation, solubility, and aggregation