title: Raphé tauopathy alters serotonin metabolism and breathing activity in terminal Tau.P301L mice: possible implications for tauopathies and Alzheimer's disease.
abstract: Tauopathies, including Alzheimer's disease are the most frequent neurodegenerative disorders in elderly people. Patients develop cognitive and behaviour defects induced by the tauopathy in the forebrain, but most also display early brainstem tauopathy, with oro-pharyngeal and serotoninergic (5-HT) defects. We studied these aspects in Tau.P301L mice, that express human mutant tau protein and develop tauopathy first in hindbrain, with cognitive, motor and upper airway defects from 7 to 8 months onwards, until premature death before age 12 months. Using plethysmography, immunohistochemistry and biochemistry, we examined the respiratory and 5-HT systems of aging Tau.P301L and control mice. At 8 months, Tau.P301L mice developed upper airway dysfunction but retained normal respiratory rhythm and normal respiratory regulations. In the following weeks, Tau.P301L mice entered terminal stages with reduced body weight, progressive limb clasping and lethargy. Compared to age 8 months, terminal Tau.P301L mice showed aggravated upper airway dysfunction, abnormal respiratory rhythm and abnormal respiratory regulations. In addition, they showed severe tauopathy in Kolliker-Fuse, raphé obscurus and raphé magnus nuclei but not in medullary respiratory-related areas. Although the raphé tauopathy concerned mainly non-5-HT neurons, the 5-HT metabolism of terminal Tau.P301L mice was altered. We propose that the progressive raphé tauopathy affects the 5-HT metabolism, which affects the 5-HT modulation of the respiratory network and therefore the breathing pattern. Then, 5-HT deficits contribute to the moribund phenotype of Tau.P301L mice, and possibly in patients suffering from tauopathies, including Alzheimer's disease.
authors.affiliation: Maturation, Plasticity, Physiology and Pathology of Respiration (MP3-Respiration), Unité Mixte de Recherche 6231, Centre National de la Recherche Scientifique, Université de la Méditerranée, Université Paul Cézanne, Faculté Saint Jérôme (Service 362), 13397 Marseille Cedex 20, France.
authors.forename: Clément
authors.initials: C
authors.lastname: Menuet
authors.forename: Peter
authors.initials: P
authors.lastname: Borghgraef
authors.forename: Valéry
authors.initials: V
authors.lastname: Matarazzo
authors.forename: Lies
authors.initials: L
authors.lastname: Gielis
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lajard
authors.forename: Nicolas
authors.initials: N
authors.lastname: Voituron
authors.forename: Christian
authors.initials: C
authors.lastname: Gestreau
authors.forename: Mathias
authors.initials: M
authors.lastname: Dutschmann
authors.forename: Fred
authors.initials: F
authors.lastname: Van Leuven
authors.forename: Gérard
authors.initials: G
authors.lastname: Hilaire
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010991:Plethysmography / Q000379:methods; D011903:Raphe Nuclei / Q000378:metabolism* / Q000503:physiopathology; D015656:Respiratory Mechanics / Q000235:genetics* / Q000502:physiology; D012701:Serotonin / Q000378:metabolism*; D024801:Tauopathies / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D016875:tau Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins; D012701:Serotonin