Document Detail


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.
MedLine Citation:
PMID:  22797329     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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 Thr(181), Ser(199), Thr(231) and Thr(235)), but not insoluble total tau and ptau were increased. Application of the Phospho-Tau SRM assay revealed that phosphorylation at Ser(396) and Ser(404) 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.
Authors:
S Flunkert; M Hierzer; T Löffler; R Rabl; J Neddens; S Duller; E L Schofield; M A Ward; M Posch; H Jungwirth; M Windisch; B Hutter-Paier
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-7-10
Journal Detail:
Title:  Neuro-degenerative diseases     Volume:  -     ISSN:  1660-2862     ISO Abbreviation:  -     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-7-16     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101189034     Medline TA:  Neurodegener Dis     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 S. Karger AG, Basel.
Affiliation:
JSW Life-Sciences GmbH, Grambach, Austria.
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