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The Journal of Neuroscience, June 13, 2007, 27(24):6552-6562; doi:10.1523/JNEUROSCI.5173-06.2007

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Neurobiology of Disease
Corticotropin-Releasing Factor Receptors Differentially Regulate Stress-Induced Tau Phosphorylation

Robert A. Rissman,1 Kuo-Fen Lee,2 Wylie Vale,2 and Paul E. Sawchenko1

1Laboratory of Neuronal Structure and Function and 2The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies and Foundation for Medical Research, La Jolla, California 92037

Correspondence should be addressed to either Robert A. Rissman or Paul E. Sawchenko, Laboratory of Neuronal Structure and Function, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, Email: rrissman{at}salk.edu or Email: sawchenko{at}salk.edu

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.

Key words: Alzheimer's disease; antalarmin corticotropin-releasing factor; corticotropin-releasing hormone; hippocampus; restraint stress; tau phosphorylation

Received Nov. 29, 2006; revised May 10, 2007; accepted May 11, 2007.

Correspondence should be addressed to either Robert A. Rissman or Paul E. Sawchenko, Laboratory of Neuronal Structure and Function, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, Email: rrissman{at}salk.edu or Email: sawchenko{at}salk.edu






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