Increased Tau Phosphorylation and Aggregation in the Hippocampus of Mice Overexpressing Corticotropin-Releasing Factor
| Autor: | Shannon N. Campbell, Cheng Zhang, Eliezer Masliah, Louise Monte, Yvette Taché, Allyson D. Roe, Robert A. Rissman, Kenner C. Rice |
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| Rok vydání: | 2014 |
| Předmět: |
Aging
Pathology Corticotropin-Releasing Hormone hippocampus Hippocampus Neurodegenerative Hippocampal formation Alzheimer's Disease Transgenic Mice stress Corticotropin-releasing hormone Receptors 2.1 Biological and endogenous factors Chronic stress Phosphorylation Aetiology Cognitive decline Kinase tau phosphorylation General Neuroscience corticotropin-releasing factor General Medicine Psychiatry and Mental health Clinical Psychology immunohistochemistry Neurological Cognitive Sciences medicine.medical_specialty Clinical Sciences tau Proteins Pathological Internal medicine Acquired Cognitive Impairment medicine Animals Kinase activity western blot Neurology & Neurosurgery electron microscopy business.industry Neurosciences Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Protein Aggregation Brain Disorders corticotropin-releasing factor receptor Endocrinology Dementia Geriatrics and Gerontology business |
| Zdroj: | Journal of Alzheimer's disease : JAD, vol 43, iss 3 |
| ISSN: | 1875-8908 1387-2877 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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