tauopathy alters serotonin metabolism and breathing activity in terminal au . P 301 L mice : Possible implications for tauopathies and Alzheimer ’ s disease

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. Abbreviations: AD, Alzheimer disease; ASp, airflow spirogram; CSp, chest pirogram; g7, genu of the facial nerve; KF, kolliker-fuse nucleus; LPB, lateral arabrachial nucleus; mcp, middle cerebellar peduncle; nA, nucleus ambiguus; n7, acial motor nucleus; nTS, nucleus tractus solitarius; PnO, pontine reticular nucleus; nR, raphé pontis nucleus; pr5DM, principal trigeminal sensory nucleus dorsoedian; Rf, respiratory frequency; RMg, raphé magnus; ROb, raphé obscurus; RPa, aphé pallidus; scp, superior cerebella peduncle; SubC, subcoeruelus nucleus; Ti, uration of inspiration; Te, duration of expiration; Ttot, total respiratory cycle duraion; VT, tidal volume; 5-HT, serotonin; 5-HIAA, 5-hydroxy-indol acid acetic; 12r, ntra-medullary rootlet of hypoglossal nerve. ∗ Corresponding author at: Mp3-Respiration Team, CRN2M, UMR 6231, CNRS – niversité Aix-Marseille II & III, Faculté Saint Jérôme, Service 362, 13397 Marseille edex 20, France. Tel. : +33 491 28 81 72; fax: +33 491 28 83 97. E-mail address: gerard.hilaire@univ-cezanne.fr (G. Hilaire). 1 Present address: Laboratoire Réponses Cellulaires et Fonctionnelles à l’Hypoxie, A2363, Université Paris13, Bobigny, France. 569-9048/$ – see front matter © 2011 Elsevier B.V. All rights reserved. oi:10.1016/j.resp. 2011.06. 030 © 2011 Elsevier B.V. All rights reserved.