title: Exaggerated phosphorylation of brain tau protein in CRH KO mice exposed to repeated immobilization stress.
abstract: Neuroendocrine and behavioral stress responses are orchestrated by corticotropin-releasing hormone (CRH) and norepinephrine (NE) synthesizing neurons. Recent findings indicate that stress may promote development of neurofibrillary pathology in Alzheimer's disease. Therefore, we investigated relationships among stress, tau protein phosphorylation, and brain NE using wild-type (WT) and CRH-knockout (CRH KO) mice. We assessed expression of phosphorylated tau (p-tau) at the PHF-1 epitope and NE concentrations in the locus coeruleus (LC), A1/C1 and A2/C2 catecholaminergic cell groups, hippocampus, amygdala, nucleus basalis magnocellularis, and frontal cortex of unstressed, singly stressed or repeatedly stressed mice. Moreover, gene expression and protein levels of tyrosine hydroxylase (TH) and CRH receptor mRNA were determined in the LC. Plasma corticosterone levels were also measured. Exposure to a single stress increases tau phosphorylation throughout the brain in WT mice when compared to singly stressed CRH KO animals. In contrast, repeatedly stressed CRH KO mice showed exaggerated tau phosphorylation relative to WT controls. We also observed differences in extent of tau phosphorylation between investigated structures, e.g. the LC and hippocampus. Moreover, CRH deficiency leads to different responses to stress in gene expression of TH, NE concentrations, CRH receptor mRNA, and plasma corticosterone levels. Our data indicate that CRH effects on tau phosphorylation are dependent on whether stress is single or repeated, and differs between brain regions. Our findings indicate that CRH attenuates mechanisms responsible for development of stress-induced tau neuropathology, particularly in conditions of chronic stress. However, the involvement of central catecholaminergic neurons in these mechanisms remains unclear and is in need of further investigation.
authors.affiliation: a Institute of Experimental Endocrinology, Biomedical Research Center , Slovak Academy of Sciences , Bratislava , Slovakia ;
authors.forename: Richard
authors.initials: R
authors.lastname: Kvetnansky
authors.affiliation: b Institute of Neuroimmunology , Slovak Academy of Sciences , Bratislava , Slovakia ;
authors.forename: Petr
authors.initials: P
authors.lastname: Novak
authors.affiliation: a Institute of Experimental Endocrinology, Biomedical Research Center , Slovak Academy of Sciences , Bratislava , Slovakia ;
authors.forename: Peter
authors.initials: P
authors.lastname: Vargovic
authors.affiliation: a Institute of Experimental Endocrinology, Biomedical Research Center , Slovak Academy of Sciences , Bratislava , Slovakia ;|c Faculty of Medicine, Institute of Physiology , Comenius University in Bratislava, Bratislava , Slovakia ;
authors.forename: Katarina
authors.initials: K
authors.lastname: Lejavova
authors.affiliation: a Institute of Experimental Endocrinology, Biomedical Research Center , Slovak Academy of Sciences , Bratislava , Slovakia ;
authors.forename: Lubica
authors.initials: L
authors.lastname: Horvathova
authors.affiliation: a Institute of Experimental Endocrinology, Biomedical Research Center , Slovak Academy of Sciences , Bratislava , Slovakia ;|c Faculty of Medicine, Institute of Physiology , Comenius University in Bratislava, Bratislava , Slovakia ;
authors.forename: Katarina
authors.initials: K
authors.lastname: Ondicova
authors.affiliation: d LDN, Labor Diagnostika Nord , Nordhorn , Germany.
authors.forename: George
authors.initials: G
authors.lastname: Manz
authors.affiliation: b Institute of Neuroimmunology , Slovak Academy of Sciences , Bratislava , Slovakia ;
authors.forename: Peter
authors.initials: P
authors.lastname: Filipcik
authors.affiliation: b Institute of Neuroimmunology , Slovak Academy of Sciences , Bratislava , Slovakia ;
authors.forename: Michal
authors.initials: M
authors.lastname: Novak
authors.affiliation: a Institute of Experimental Endocrinology, Biomedical Research Center , Slovak Academy of Sciences , Bratislava , Slovakia ;|c Faculty of Medicine, Institute of Physiology , Comenius University in Bratislava, Bratislava , Slovakia ;
authors.forename: Boris
authors.initials: B
authors.lastname: Mravec
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism; D012149:Restraint, Physical; D013315:Stress, Psychological / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D016875:tau Proteins; D003346:Corticotropin-Releasing Hormone
keywords: Alzheimer's disease; cornu amonis; corticosterone; locus coeruleus; norepinephrine; nucleus basalis magnocellularis