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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

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
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

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.

0270-6474
18175-89
Mellone, Manuela
6e5c0e65-74a2-4cfc-b33f-442a68f5cf9e
Kestoras, Dimitra
9c53bae1-146f-47de-9224-3ab493ce7299
Andrews, Melissa R.
ae987a2f-878e-4ae3-a7a3-a7170712096c
Dassie, Elisa
18566ce2-048b-47b8-928b-1c2baccf149a
Crowther, R. Anthony
c1d12b65-e712-4634-ab13-aebb60e26f94
Stokin, Gorazd B.
4a5c0779-ad67-43cc-b60b-cf424403dea9
Tinsley, Jon
1e297f75-456b-4aff-8f3c-dc9b176bdd47
Horne, Graeme
04115110-359f-4070-ac27-f8baaea02ada
Goedert, Michel
2e92de4a-529b-4c29-9eae-d7258744f52f
Tolkovsky, Aviva M.
c7bfa481-5040-4558-8100-d83b8aff45b2
Spillantini, Maria Grazia
33bc74d0-8e18-47a9-850a-c65fcbe76ff7
Mellone, Manuela
6e5c0e65-74a2-4cfc-b33f-442a68f5cf9e
Kestoras, Dimitra
9c53bae1-146f-47de-9224-3ab493ce7299
Andrews, Melissa R.
ae987a2f-878e-4ae3-a7a3-a7170712096c
Dassie, Elisa
18566ce2-048b-47b8-928b-1c2baccf149a
Crowther, R. Anthony
c1d12b65-e712-4634-ab13-aebb60e26f94
Stokin, Gorazd B.
4a5c0779-ad67-43cc-b60b-cf424403dea9
Tinsley, Jon
1e297f75-456b-4aff-8f3c-dc9b176bdd47
Horne, Graeme
04115110-359f-4070-ac27-f8baaea02ada
Goedert, Michel
2e92de4a-529b-4c29-9eae-d7258744f52f
Tolkovsky, Aviva M.
c7bfa481-5040-4558-8100-d83b8aff45b2
Spillantini, Maria Grazia
33bc74d0-8e18-47a9-850a-c65fcbe76ff7

Mellone, Manuela, Kestoras, Dimitra, Andrews, Melissa R., Dassie, Elisa, Crowther, R. Anthony, Stokin, Gorazd B., Tinsley, Jon, Horne, Graeme, Goedert, Michel, Tolkovsky, Aviva M. and Spillantini, Maria Grazia (2013) 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. Journal of Neuroscience, 33 (46), 18175-89. (doi:10.1523/JNEUROSCI.4933-12.2013).

Record type: Article

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.

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Published date: 13 November 2013

Identifiers

Local EPrints ID: 412465
URI: https://eprints.soton.ac.uk/id/eprint/412465
ISSN: 0270-6474
PURE UUID: 2cfc1d76-21c0-450b-8ab7-eba2d22c3713
ORCID for Melissa R. Andrews: ORCID iD orcid.org/0000-0001-5960-5619

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Date deposited: 17 Jul 2017 13:49
Last modified: 20 Jul 2019 00:28

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