[Abstract Title]. - Society for Neuroscience

Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 245.7/O1
Topic: C.01.h. Tau
Support: American Federation for Aging Research
NIH Grant DK26741
Ellison Medical Foundation
Clayton Medical Research Foundation
Title: CRF receptor mediation of repeated stress effects on tau phosphorylation and solubility
Authors: *R. A. RISSMAN, N. J. JUSTICE, P. E. SAWCHENKO;
Lab. Neuronal Structure & Func, The Salk Inst., La Jolla, CA
Abstract: Exposure and/or sensitivity to stress may confer increased risk of Alzheimer's Disease
(AD). Although the specific links between stress and AD pathogenesis remain unsettled, our
recent data provide evidence for a differential involvement of corticotropin-releasing factor
receptors (CRFR1 and 2) in the regulation of hippocampal tau phosphorylation (tau-P) induced
by acute exposure to an emotional stressor, restraint. Relative to wild type (wt) controls, tau-P
responses were lacking in CRFR1-deficient mice, and exaggerated in CRFR2 mutants. Because
acute stress-induced tau-P is a transient phenomenon, we used anatomical and biochemical
analyses to assess the relationship between CRFRs and tau-P after exposure to repeated restraint
stress (14 daily exposures). Dual immunofluorescence labeling in a transgenic CRFR1 reporter
mouse line exposed to repeated stress revealed substantial overlap between hippocampal CRFR1
expression and cells positive for phosphorylated tau (PHF-1). We next used Western analyses of
soluble (RAB) and detergent-soluble (RIPA) fractions of hippocampal extracts to explore the
pathogenic potential of stress-induced tau-P by comparing the effects and CRFR-dependence of
acute versus repeated restraint stress exposure on the persistence of tau-P and its solubility.
Whereas hippocampal tau-P was comparably increased at 20 min after a single (acute) or the last
of 14 (repeated) restraint episode(s), chronic elevations (i.e., at 24 hr after stress) were detected
only in the repeated condition. Moreover, a portion of tau-P in extracts from repeatedly stressed
mice was present in an insoluble form (RIPA fraction), while acute restraint-induced tau-P was
detectable in only the soluble (RAB) fraction. Relative to wt controls, each of these stress effects
on tau-P and solubility was comparable, if not enhanced, in CRFR2-deficient mice, but was not
detectable in CRFR1 or double knockout animals. Analysis of RIPA fractions from wt and
CRFR2 animals by negative staining at the EM level and identified globular aggregates that
displayed positive immunogold labeling for early conformational changes in tau (MC-1 and Alz-
50), as well as tau-P (PHF-1). These results further support a push-pull involvement of CRFRs in
regulating restraint stress-induced tau-P. Given that repeated stress exposure results in chronic
increases in hippocampal tau-P and its sequestration in an insoluble (and potentially pre-