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000136827 0247_ $$2doi$$a10.1016/j.neurobiolaging.2012.10.024
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000136827 0247_ $$2ISSN$$a1558-1497
000136827 037__ $$aDZNE-2020-03149
000136827 041__ $$aEnglish
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000136827 1001_ $$0P:(DE-2719)2810335$$aMessing, Lars$$b0$$eFirst author$$udzne
000136827 245__ $$aCascade of tau toxicity in inducible hippocampal brain slices and prevention by aggregation inhibitors.
000136827 260__ $$aAmsterdam [u.a.]$$bElsevier Science$$c2013
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000136827 520__ $$aMislocalization and aggregation of the axonal protein tau are hallmarks of Alzheimer's disease and other tauopathies. Here, we studied the relationship between tau aggregation, loss of spines and neurons, and reversibility by aggregation inhibitors. To this end we established an in vitro model of tauopathy based on regulatable transgenic hippocampal organotypic slice cultures prepared from mice expressing proaggregant Tau repeat domain with mutation ΔK280 (Tau(RD)ΔK). Transgene expression was monitored by a bioluminescence reporter assay. We observed abnormal tau phosphorylation and mislocalization of exogenous and endogenous tau into the somatodendritic compartment. This was paralleled by a reduction of dendritic spines, altered dendritic spine morphology, dysregulation of Ca(++) dynamics and elevated activation of microglia. Neurotoxicity was mediated by Caspase-3 activation and correlated with the expression level of proaggregant Tau(RD)ΔK. Finally, tau aggregates appeared in areas CA1 and CA3 after three weeks in vitro. Neurodegeneration was relieved by aggregation inhibitors or by switching off transgene expression. Thus the slice culture model is suitable for monitoring the development of tauopathy and the therapeutic benefit of antiaggregation drugs.
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000136827 650_7 $$2NLM Chemicals$$aMapt protein, mouse
000136827 650_7 $$2NLM Chemicals$$atau Proteins
000136827 650_2 $$2MeSH$$aAnimals
000136827 650_2 $$2MeSH$$aCalcium Signaling
000136827 650_2 $$2MeSH$$aCells, Cultured
000136827 650_2 $$2MeSH$$aDimerization
000136827 650_2 $$2MeSH$$aHippocampus: pathology
000136827 650_2 $$2MeSH$$aHippocampus: physiopathology
000136827 650_2 $$2MeSH$$aMice
000136827 650_2 $$2MeSH$$aMice, Transgenic
000136827 650_2 $$2MeSH$$aNeurons: pathology
000136827 650_2 $$2MeSH$$aTauopathies: physiopathology
000136827 650_2 $$2MeSH$$atau Proteins: metabolism
000136827 7001_ $$0P:(DE-2719)2810343$$aDecker, Jochen Martin$$b1$$udzne
000136827 7001_ $$0P:(DE-2719)2813357$$aJoseph, Maria$$b2$$udzne
000136827 7001_ $$0P:(DE-2719)2541671$$aMandelkow, Eckhard$$b3$$udzne
000136827 7001_ $$0P:(DE-2719)2541658$$aMandelkow, Eva-Maria$$b4$$eLast author$$udzne
000136827 77318 $$2Crossref$$3journal-article$$a10.1016/j.neurobiolaging.2012.10.024$$b : Elsevier BV, 2013-05-01$$n5$$p1343-1354$$tNeurobiology of Aging$$v34$$x0197-4580$$y2013
000136827 773__ $$0PERI:(DE-600)1498414-3$$a10.1016/j.neurobiolaging.2012.10.024$$gVol. 34, no. 5, p. 1343 - 1354$$n5$$p1343-1354$$q34:5<1343 - 1354$$tNeurobiology of aging$$v34$$x0197-4580$$y2013
000136827 8567_ $$2Pubmed Central$$uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4984976
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