Corticotropin-releasing factor receptors differentially regulate stress-induced tau phosphorylation.
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.
Rissman
Robert A
RA
Laboratory of Neuronal Structure and Function, The Salk Institute for Biological Studies and Foundation for Medical Research, La Jolla, California 92037, USA. rrissman@salk.edu
Lee
Kuo-Fen
KF
Vale
Wylie
W
Sawchenko
Paul E
PE
D000315:Adrenalectomy / Q000379:methods; D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D003345:Corticosterone / Q000008:administration & dosage; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D047468:Immunoprecipitation / Q000379:methods; D007276:Injections, Intraventricular / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage; D011758:Pyrroles / Q000008:administration & dosage; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D013312:Stress, Physiological / Q000378:metabolism*; D013997:Time Factors; D016875:tau Proteins / Q000378:metabolism*
D000911:Antibodies, Monoclonal; C085349:PHF-1 monoclonal antibody; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; C103016:antalarmin; D016875:tau Proteins; D003346:Corticotropin-Releasing Hormone; D011494:Protein Kinases; D003345:Corticosterone