title: Tauopathy in transgenic (SHR72) rats impairs function of central noradrenergic system and promotes neuroinflammation.
abstract: BACKGROUND
  Brain norepinephrine (NE) plays an important role in the modulation of stress response and neuroinflammation. Recent studies indicate that in Alzheimer's disease (AD), the tau neuropathology begins in the locus coeruleus (LC) which is the main source of brain NE. Therefore, we investigated the changes in brain NE system and also the immune status under basal and stress conditions in transgenic rats over-expressing the human truncated tau protein.
  
  
  METHODS
  Brainstem catecholaminergic cell groups (LC, A1, and A2) and forebrain subcortical (nucleus basalis of Meynert), hippocampal (cornu ammonis, dentate gyrus), and neocortical areas (frontal and temporal association cortices) were analyzed for NE and interleukin 6 (IL-6) mRNA levels in unstressed rats and also in rats exposed to single or repeated immobilization. Moreover, gene expression of NE-biosynthetic enzyme, tyrosine hydroxylase (TH), and several pro- and anti-inflammatory mediators were determined in the LC.
  
  
  RESULTS
  It was found that tauopathy reduced basal NE levels in forebrain areas, while the gene expression of IL-6 was increased in all selected areas at the same time. The differences between wild-type and transgenic rats in brain NE and IL-6 mRNA levels were observed in stressed animals as well. Tauopathy increased also the gene expression of TH in the LC. In addition, the LC exhibited exaggerated expression of pro- and anti-inflammatory mediators (IL-6, TNFα, inducible nitric oxide synthases 2 (iNOS2), and interleukin 10 (IL-10)) in transgenic rats suggesting that tauopathy affects also the immune background in LC. Positive correlation between NE and IL-6 mRNA levels in cornu ammonis in stressed transgenic animals indicated the reduction of anti-inflammatory effect of NE.
  
  
  CONCLUSIONS
  Our data thus showed that tauopathy alters the functions of LC further leading to the reduction of NE levels and exaggeration of neuroinflammation in forebrain. These findings support the assumption that tau-related dysfunction of LC activates the vicious circle perpetuating neurodegeneration leading to the development of AD.
authors.affiliation: Institute of Experimental Endocrinology, Slovak Academy of Sciences, Vlarska 3, 833 06, Bratislava, Slovakia. boris.mravec@savba.sk.|Institute of Physiology, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia. boris.mravec@savba.sk.
authors.forename: Boris
authors.initials: B
authors.lastname: Mravec
authors.affiliation: Institute of Experimental Endocrinology, Slovak Academy of Sciences, Vlarska 3, 833 06, Bratislava, Slovakia. katarina.lejavova@fmed.uniba.sk.|Institute of Physiology, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia. katarina.lejavova@fmed.uniba.sk.
authors.forename: Katarina
authors.initials: K
authors.lastname: Lejavova
authors.affiliation: Institute of Experimental Endocrinology, Slovak Academy of Sciences, Vlarska 3, 833 06, Bratislava, Slovakia. peter.vargovic@savba.sk.
authors.forename: Peter
authors.initials: P
authors.lastname: Vargovic
authors.affiliation: Institute of Experimental Endocrinology, Slovak Academy of Sciences, Vlarska 3, 833 06, Bratislava, Slovakia. katarina.ondicova@fmed.uniba.sk.|Institute of Physiology, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia. katarina.ondicova@fmed.uniba.sk.
authors.forename: Katarina
authors.initials: K
authors.lastname: Ondicova
authors.affiliation: Institute of Experimental Endocrinology, Slovak Academy of Sciences, Vlarska 3, 833 06, Bratislava, Slovakia. lubica.lackovicova@savba.sk.
authors.forename: Lubica
authors.initials: L
authors.lastname: Horvathova
authors.affiliation: Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia. petr.novak@savba.sk.|Axon Neuroscience SE, Bratislava, Slovakia. petr.novak@savba.sk.
authors.forename: Petr
authors.initials: P
authors.lastname: Novak
authors.affiliation: LDN, Labor Diagnostika Nord, Nordhorn, Germany. gmanz@ldn.de.
authors.forename: Georg
authors.initials: G
authors.lastname: Manz
authors.affiliation: Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia. peter.filipcik@savba.sk.|Axon Neuroscience SE, Bratislava, Slovakia. peter.filipcik@savba.sk.
authors.forename: Peter
authors.initials: P
authors.lastname: Filipcik
authors.affiliation: Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia. michal.novak@savba.sk.|Axon Neuroscience SE, Bratislava, Slovakia. michal.novak@savba.sk.
authors.forename: Michal
authors.initials: M
authors.lastname: Novak
authors.affiliation: Institute of Experimental Endocrinology, Slovak Academy of Sciences, Vlarska 3, 833 06, Bratislava, Slovakia. richard.kvetnansky@savba.sk.
authors.forename: Richard
authors.initials: R
authors.lastname: Kvetnansky
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004660:Encephalitis / Q000209:etiology*; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D008297:Male; D042282:Microdissection; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009638:Norepinephrine / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D055647:Rats, Transgenic; D024801:Tauopathies / Q000150:complications / Q000235:genetics / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D052247:Nitric Oxide Synthase Type II; D014446:Tyrosine 3-Monooxygenase; D009638:Norepinephrine