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

Nora Lemke, Valeria Melis, Dilyara Lauer, Mandy Magbagbeolu, Boris Neumann, Charles R Harrington, Gernot Riedel, Claude M. Wischik, Franz Theuring, Karima Schwab (Corresponding Author)

Research output: Contribution to journalArticle

Abstract

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 non-phosphorylated 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, while endogenous mouse tau is virtually absent from synapses. Cytosolic tau was resistant to solubilisation 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. Mass spectrometry corroborated that synaptosomal tau is non-phosphorylated. Tau enriched in the synapse of line 66 mice, therefore, appears to be in an oligomeric and non-phosphorylated state, and one that could have a direct impact on cognitive function.
Original languageEnglish
JournalJournal of Biological Chemistry
Early online date30 Oct 2020
DOIs
Publication statusE-pub ahead of print - 30 Oct 2020

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