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Original Paper

Elevated Levels of Soluble Total and Hyperphosphorylated Tau Result in Early Behavioral Deficits and Distinct Changes in Brain Pathology in a New Tau Transgenic Mouse Model

Flunkert S.a · Hierzer M.a · Löffler T.a · Rabl R.a · Neddens J.a · Duller S.a · Schofield E.L.b · Ward M.A.b · Posch M.a · Jungwirth H.c · Windisch M.a · Hutter-Paier B.a

Author affiliations

aJSW Life-Sciences GmbH, Grambach, Austria; bProteome Sciences plc., London, UK; cKarl Franzens University, Graz, Austria

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Neurodegener Dis 2013;11:194-205

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Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: December 20, 2011
Accepted: March 16, 2012
Published online: July 10, 2012
Issue release date: April 2013

Number of Print Pages: 12
Number of Figures: 6
Number of Tables: 0

ISSN: 1660-2854 (Print)
eISSN: 1660-2862 (Online)

For additional information: https://www.karger.com/NDD

Abstract

Tauopathies, characterized by hyperphosphorylation and aggregation of tau protein, include frontotemporal dementias and Alzheimer's disease. To explore disease mechanisms and investigate potential treatments, we generated a transgenic (tg) mouse line overexpressing human tau441 with V337M and R406W mutations. Biochemical characterization of these TMHT (Thy-1 mutated human tau) mice showed a significant increase in human transgene expression relative to endogenous murine tau by Western blot and multi-array immunosorbent assay. Only soluble total tau and phosphorylated tau (ptau at residue Thr181, Ser199, Thr231 and Thr235), but not insoluble total tau and ptau were increased. Application of the Phospho-Tau SRM assay revealed that phosphorylation at Ser396 and Ser404 in soluble tau in the presence of the R406W mutation was at baseline levels in the cortex of TMHT mice compared to non-tg littermates. Histological analyses showed a progressive increase in human tau protein in the amygdala over age, while hippocampal tau levels remained constant from 2 months onwards. Behavioral testing of TMHT mice in the Morris water maze revealed a distinct progressive spatial learning impairment starting already at 5 months of age. Furthermore, we showed that the TMHT mice have early olfactory deficits. These impairments are unbiased by any motor disturbance or lack of motivation. Our results prove that combination of the V337M and R406W mutations of tau accelerates human tau phosphorylation and induces tau pathology as well as cognitive deficits, making this model a suitable tool for basic research on tau as well as in vivo drug testing.

© 2012 S. Karger AG, Basel


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Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: December 20, 2011
Accepted: March 16, 2012
Published online: July 10, 2012
Issue release date: April 2013

Number of Print Pages: 12
Number of Figures: 6
Number of Tables: 0

ISSN: 1660-2854 (Print)
eISSN: 1660-2862 (Online)

For additional information: https://www.karger.com/NDD


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Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
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