Differential compartmental processing and phosphorylation of pathogenic human tau and native mouse tau in the line 66 model of frontotemporal dementia.

Autor:	Lemke N; Charité-Universitätsmedizin Berlin, Berlin, Germany; Bundesanstalt für Materialforschung und-prüfung, Berlin, Germany., Melis V; School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom., Lauer D; Charité-Universitätsmedizin Berlin, Berlin, Germany., Magbagbeolu M; Charité-Universitätsmedizin Berlin, Berlin, Germany., Neumann B; Charité-Universitätsmedizin Berlin, Berlin, Germany; Proteome Factory AG, Berlin, Germany., Harrington CR; School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom; TauRx Therapeutics Ltd., Aberdeen, United Kingdom., Riedel G; School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom., Wischik CM; School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom; TauRx Therapeutics Ltd., Aberdeen, United Kingdom., Theuring F; Charité-Universitätsmedizin Berlin, Berlin, Germany., Schwab K; Charité-Universitätsmedizin Berlin, Berlin, Germany. Electronic address: karima.schwab@charite.de.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2020 Dec 25; Vol. 295 (52), pp. 18508-18523. Date of Electronic Publication: 2020 Oct 30.
DOI:	10.1074/jbc.RA120.014890
Abstrakt:	Synapse loss is associated with motor and cognitive decline in multiple neurodegenerative disorders, and the cellular redistribution of tau is related to synaptic impairment in tauopathies, such as Alzheimer's disease and frontotemporal dementia. Here, we examined the cellular distribution of tau protein species in human tau overexpressing line 66 mice, a transgenic mouse model akin to genetic variants of frontotemporal dementia. Line 66 mice express intracellular tau aggregates in multiple brain regions and exhibit sensorimotor and motor learning deficiencies. Using a series of anti-tau antibodies, we observed, histologically, that nonphosphorylated transgenic human tau is enriched in synapses, whereas phosphorylated tau accumulates predominantly in cell bodies and axons. Subcellular fractionation confirmed that human tau is highly enriched in insoluble cytosolic and synaptosomal fractions, whereas endogenous mouse tau is virtually absent from synapses. Cytosolic tau was resistant to solubilization with urea and Triton X-100, indicating the formation of larger tau aggregates. By contrast, synaptic tau was partially soluble after Triton X-100 treatment and most likely represents aggregates of smaller size. MS corroborated that synaptosomal tau is nonphosphorylated. Tau enriched in the synapse of line 66 mice, therefore, appears to be in an oligomeric and nonphosphorylated state, and one that could have a direct impact on cognitive function. Competing Interests: Conflict of interest—This work was sponsored by WisTa Laboratories Ltd., an affiliate of TauRx Therapeutics Ltd. C. R. H. and C. M. W. are employees and officers of TauRx Therapeutics Ltd. (© 2020 Lemke et al.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu