TNAP upregulation is a critical factor in Tauopathies and its blockade ameliorates neurotoxicity and increases life-expectancy
Publisher
ElsevierDate
2022-01-19Citation
Neurobiology of Disease 165. (2022): 105632ISSN
0969-9961 (print)Funded by
This work was supported by funding from the following: Spanish Ministry of Economy and Competitiveness RTI2018-095753-B-I00 (to M.D.-H.), BFU2016-77885-P (to F.H.) and PGC2018-096177-B-I00 (to J.A.); European Union H2020 program H2020-MSCA-ITN-2017 number 766124 (to M.D-H); European Regional Development Funds from the Comunidad de Madrid S2017/BMD-3700 (NEUROMETAB-CM) (to F.H.); UCM-Santander Central Hispano Bank PR41/17–21,014 (to M.D-H); CIBERNED-ISCIII; and the Fundación R. Areces (to F.H.). A.S-S was hired by RTI2018-095753-B-I00 grant and as postdoctoral researcher by UCM (CT48/19), C.dL. and C.B. were hired by H2020-MSCA-ITN-2017 (grant number 766124), and J M-R had a fellowship from the Fundación La Caixa. This work was supported in part by ERDFProject
Gobierno de España. RTI2018-095753-B-I00; Gobierno de España. BFU2016-77885- P; Gobierno de España. PGC2018-096177-B-I00; info:eu-repo/grantAgreement/EC/H2020/766124/EU/MSCA-ITN; Comunidad de Madrid. S2017/BMD-3700/NEUROMETAB-CMEditor's Version
https://doi.org/10.1016/j.nbd.2022.105632Subjects
Muscarinic receptor M1; Neuronal death; Tau spreading; Levamisole; PS19; Biología y Biomedicina / BiologíaRights
© 2022 The Authors. Published by Elsevier IncEsta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
Tauopathies are a family of neurodegenerative diseases characterized by the presence of abnormally hyperphosphorylated Tau protein. Several studies have proposed that increased extracellular Tau (eTau) leads to the spread of cerebral tauopathy. However, the molecular mechanisms underlying eTau-induced neurotoxicity remain unclear. Previous in vitro studies reported that the ecto-enzyme tissue-nonspecific alkaline phosphatase (TNAP) dephosphorylate eTau at different sites increasing its neurotoxicity. Here, we confirm TNAP protein upregulation in the brains of Alzheimer's patients and found a similar TNAP increase in Pick's disease patients and P301S mice, a well-characterized mouse model of tauopathies. Interestingly, the conditional overexpression of TNAP causes intracellular Tau hyperphosphorylation and aggregation in cells neighbouring those overexpressing the ectoenzyme. Conversely, the genetic disruption of TNAP reduced the dephosphorylation of eTau and decreased neuronal hyperactivity, brain atrophy, and hippocampal neuronal death in P301S mice. TNAP haploinsufficiency in P301S mice prevents the decreased anxiety-like behaviour, motor deficiency, and increased memory capacity and life expectancy. Similar results were observed by the in vivo pharmacological blunting of TNAP activity. This study provides the first in vivo evidence demonstrating that raised TNAP activity is critical for Tau-induced neurotoxicity and suggest that TNAP blockade may be a novel and efficient therapy to treat tauopathies
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Google Scholar:Sebastián-Serrano, Álvaro
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Merchán-Rubira, Jesús
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Di Lauro, Caterina
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Bianchi, Carolina
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Soria-Tobar, Lucía
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Narisawa, Sonoko
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Millán, José L.
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Ávila, Jesús
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Hernández, Félix
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Diaz-Hernandez, Miguel
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