Ozcelik, Sefika, Skachokova, Zhiva, Fraser, Graham, Abramowski, Dorothee, Sprenger, Frederik, Clavaguera, Florence, Probst, Alphonse, Kappos, Ludwig, Frank, Stephan, Müller, Mathias, Staufenbiel, Matthias, Goedert, Michel, Tolnay, Markus and Winkler, David T (2016) Co-expression of truncated and full-length tau induces severe neurotoxicity. Molecular Psychiatry.

Abstract

Hyperphosphorylated and aggregated tau protein constitutes the main pathological hallmark of tauopathies, including Alzheimer’s disease (AD). While proteolytically cleaved peptides play a central role in various neurodegenerative disorders, the importance of tau fragmentation for the pathogenesis of tauopathies is still being debated.
Here we studied the toxicity of a human 3 repeat tau151-421 fragment (tau) in vivo, using a novel inducible transgenic mouse model (TAU62 mice). These mice developed a slowly progressive motor phenotype and histopathological lesions compatible with axonal damage. To mimic the disease situation, where tau fragmentation occurs in presence of full-length tau, we co-expressed tau with human full-length human P301S tau (P301SxTAU62 mice). This resulted in severe neuronal dysfunction with rapidly progressive motor palsy and a wide spectrum of tauopathy associated changes, notably in the absence of tau tangles or filaments. Strikingly, these changes were widely reversible when tau expression was halted. In contrast, co-expression of full-length human 3 repeat tau with P301S tau (P301SxALZ31 mice) did not result in a drastic phenotype.
We conclude that tau fragments can potentiate full-length tau toxicity in vivo and in this way may contribute to the pathogenesis of tauopathies. The fact that this happened in the absence of tangle formation may reflect an early phase of tauopathies, in which functional changes induced by yet soluble toxic tau species can still be partly reversible by curative treatments.

Item Type:	Article
Keywords:	Alzheimer’s disease; Tauopathy; Aggregation; Tau fragmentation; Axonopathy; Transgenic mouse models
Date Deposited:	04 May 2016 23:45
Last Modified:	04 May 2016 23:45
URI:	https://oak.novartis.com/id/eprint/11445