Corticotropin-Releasing Factor Receptors Differentially Regulate Stress-Induced Tau Phosphorylation

• Published in: The Journal of neuroscience Vol. 27; no. 24; pp. 6552 - 6562
• Main Authors: Rissman, Robert A, Lee, Kuo-Fen, Vale, Wylie, Sawchenko, Paul E
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 13.06.2007; Society for Neuroscience
• Subjects: Adrenalectomy - methods; Analysis of Variance; Animals; Antibodies, Monoclonal - metabolism; Corticosterone - administration & dosage; Corticotropin-Releasing Hormone - pharmacology; Gene Expression Regulation - drug effects; Immunoprecipitation - methods; Injections, Intraventricular - methods; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphorylation; Protein Kinases - metabolism; Pyrimidines - administration & dosage; Pyrroles - administration & dosage; Receptors, Corticotropin-Releasing Hormone - antagonists & inhibitors; Receptors, Corticotropin-Releasing Hormone - deficiency; Receptors, Corticotropin-Releasing Hormone - physiology; Stress, Physiological - metabolism; tau Proteins - metabolism; Time Factors
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.5173-06.2007

Hyperphosphorylation of the microtubule-associated protein tau is a key event in the development of Alzheimer's disease (AD) neuropathology. Acute stress can induce hippocampal tau phosphorylation (tau-P) in rodents, but the mechanisms and pathogenic relevance of this response are unclear. Here, we find that hippocampal tau-P elicited by an acute emotional stressor, restraint, was not affected by preventing the stress-induced rise in glucocorticoids but was blocked by genetic or pharmacologic disruption of signaling through the type 1 corticotropin-releasing factor receptor (CRFR1). Conversely, these responses were exaggerated in CRFR2-deficient mice. Parallel CRFR dependence was seen in the stress-induced activation of specific tau kinases. Repeated stress exposure elicited cumulative effects on tau-P and its sequestration in an insoluble, and potentially pathogenic, form. These findings support differential regulatory roles for CRFRs in an AD-relevant form of neuronal plasticity and may link datasets documenting alterations in the CRF signaling system in AD and implicating chronic stress as a risk factor in age-related neurological disorders.