Neurotoxic impact of protein fragmentation and aggregation in tauopathy mouse models

The microtubule-associated protein tau and its pathological modification constitute the central pathology of various human neurodegenerative diseases, including Alzheimer’s disease (AD), collectively termed ‘tauopathies’. Abundant hyperphosphorylation and aggregation of tau is a disease-defining hallmark, yet the underlying pathogenic and pathophysiological processes have remained only partly understood. In addition, protein fragmentation is a frequently observed phenomenon in the course of various neurodegenerative diseases; however, the contribution of tau fragmentation to the pathogenesis of tauopathies is still a matter of debate. In our novel inducible mouse model, co-expression of truncated and full-length human tau provokes axonal transport failure, mitochondrial mislocalization, disruption of the Golgi apparatus and dysregulation of synaptic proteins associated with extensive nerve cell loss and a severe neurological phenotype as early as 3 weeks of age. Of note, this was paralleled only by the formation of soluble oligomeric tau species, and no insoluble filamentous tau aggregates; therewith, identifying oligomeric tau species as toxic key players in tau pathology. Despite continuous full-length tau expression, mice recovered from the neurotoxic insult once truncated tau expression was halted. The induction of drastic but reversible neurotoxicity highlights the neurotoxic potential of tau fragments as pathogenic mediators in neurodegenerative disorders. The present work implicates the complexity of protein fragmentation and oligomerization and their neurotoxic impact in the context of tauopathies and aims for a better understanding of the cellular mechanisms underlying tau toxicity.