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Tau pathology is present in vivo and develops in vitro in sensory neurons from human P301S Tau transgenic mice : a system for screening drugs against tauopathies

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Date
13/11/2013
Author
Mellone, Manuela
Kestoras, Dimitra
Andrews, Melissa Renee
Dassie, Elisa
Crowther, R. Anthony
Stokin, Gorazd B
Tinsley, Jon
Horne, Graeme
Goedert, Michel
Tolkovsky, Aviva M.
Spillantini, Maria Grazia
Keywords
R Medicine
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Abstract
Intracellular tau aggregates are the neuropathological hallmark of several neurodegenerative diseases, including Alzheimer's disease, progressive supranuclear palsy, and cases of frontotemporal dementia, but the link between these aggregates and neurodegeneration remains unclear. Neuronal models recapitulating the main features of tau pathology are necessary to investigate the molecular mechanisms of tau malfunction, but current models show little and inconsistent spontaneous tau aggregation. We show that dorsal root ganglion (DRG) neurons in transgenic mice expressing human P301S tau (P301S-htau) develop tau pathology similar to that found in brain and spinal cord and a significant reduction in mechanosensation occurs before detectable fibrillar tau formation. DRG neuronal cultures established from adult P301S-htau mice at different ages retained the pattern of aberrant tau found in vivo. Moreover, htau became progressively hyperphosphorylated over 2 months in vitro beginning with nonsymptomatic neurons, while hyperphosphorylated P301S-htau-positive neurons from 5-month-old mice cultured for 2 months died preferentially. P301S-htau-positive neurons grew aberrant axons, including spheroids, typically found in human tauopathies. Neurons cultured at advanced stages of tau pathology showed a 60% decrease in the fraction of moving mitochondria. SEG28019, a novel O-GlcNAcase inhibitor, reduced steady-state pSer396/pSer404 phosphorylation over 7 weeks in a significant proportion of DRG neurons showing for the first time the possible beneficial effect of prolonged dosing of O-GlcNAcase inhibitor in vitro. Our system is unique in that fibrillar tau forms without external manipulation and provides an important new tool for understanding the mechanisms of tau dysfunction and for screening of compounds for treatment of tauopathies.
Citation
Mellone , M , Kestoras , D , Andrews , M R , Dassie , E , Crowther , R A , Stokin , G B , Tinsley , J , Horne , G , Goedert , M , Tolkovsky , A M & Spillantini , M G 2013 , ' Tau pathology is present in vivo  and develops i n vitro in sensory neurons from human P301S Tau transgenic mice : a system for screening drugs against tauopathies ' , The Journal of Neuroscience , vol. 33 , no. 46 , pp. 18175-18189 . https://doi.org/10.1523/JNEUROSCI.4933-12.2013
Publication
The Journal of Neuroscience
Status
Peer reviewed
DOI
https://doi.org/10.1523/JNEUROSCI.4933-12.2013
ISSN
0270-6474
Type
Journal article
Rights
Copyright © 2013 the authors. This is an article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for noncommercial use, provided the original work is properly cited
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  • University of St Andrews Research
URI
http://hdl.handle.net/10023/6768

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