Increased Tau Phosphorylation and Aggregation in the Hippocampus of Mice Overexpressing Corticotropin-Releasing Factor

Article type: Research Article

Authors: Campbell, Shannon N.^a | Zhang, Cheng^a | Monte, Louise^a | Roe, Allyson D.^a | Rice, Kenner C.^c | Taché, Yvette^{d; e} | Masliah, Eliezer^{a; b} | Rissman, Robert A.^{a; *}

Affiliations: [a] Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA | [b] Department of Pathology, University of California, San Diego, La Jolla, CA, USA | [c] Chemical Biology Research Branch, National Institutes on Drug Abuse and Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA | [d] Center for Neurobiology of Stress and Women's Health, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA | [e] CURE Digestive Diseases Research Center and Center for Neurobiology of Stress, Digestive Diseases Division at the University of California Los Angeles, and VA Greater Los Angeles Health Care System Los Angeles, CA, USA

Correspondence: [*] Correspondence to: Robert A. Rissman, Department of Neurosciences, UCSD School of Medicine, 9500 Gilman Drive, MTF 314 M/C 0624, La Jolla, CA 92037-0624, USA. Tel.: +1 858 246 0140; Fax: +1 858 246 0139; E-mail: rrissman@ucsd.edu.

Abstract: Clinical and basic science research suggests that stress and/or changes in central stress signaling intermediates may be involved in Alzheimer's disease (AD) pathogenesis. Although the links between stress and AD remain unsettled, data from our group and others have established that stress exposure in rodents may confer susceptibility to AD pathology by inducing hippocampal tau phosphorylation (tau-P). Work in our laboratory has shown that stress-induced tau-P requires activation of the type-1 corticotropin-releasing factor receptor (CRFR1). CRF overexpressing (CRF-OE) mice are a model of chronic stress that display cognitive impairment at 9–10 month of age. In this study we used 6–7 month old CRF-OE mice to examine whether sustained exposure to CRF and stress steroids would impact hippocampal tau-P and kinase activity in the presence or absence of the CRFR1-specific antagonist, R121919, given daily for 30 days. CRF-OE mice had significantly elevated tau-P compared to wild type (WT) mice at the AT8 (S202/T204), PHF-1 (S396/404), S262, and S422 sites. Treating CRF-OE mice with R121919 blocked phosphorylation at the AT8 (S202/T204) and PHF-1 (S396/404) sites, but not at the S262 and S422 sites and reduced phosphorylation of c-Jun N Terminal Kinase (JNK). Examination of hippocampal extracts from CRF-OE mice at the ultrastructural level revealed negatively stained round/globular aggregates that were positively labeled by PHF-1. These data suggest critical roles for CRF and CRFR1 in tau-P and aggregation and may have implications for the development of AD cognitive decline.

Keywords: Alzheimer's disease, corticotropin-releasing factor (CRF), corticotropin-releasing factor receptor (CRFR), electron microscopy, hippocampus, immunohistochemistry, stress, tau phosphorylation (tau-P), western blot

DOI: 10.3233/JAD-141281

Journal: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 967-976, 2015