Mechanisms of tau fragmentation, aggregation and degradation in transgenic mouse models

Neurodegenerative disorders with abnormal accumulation of tau protein are termed “tauopathies”. These disorders, including Alzheimer’s disease, are affecting more than 20 million people worldwide. Although their pathogenesis is related to the formation of tau aggregates, the exact molecular mechanisms underlying these disorders are still not well understood. The main aim of my thesis was to characterize the mechanisms of tau accumulation and removal. I therefore studied the role of truncated tau in the development of taupathies and tested whether induction of autophagy, a well-known catabolic process, may be sufficient to reverse tau accumulation and ameliorate tau-induced pathology.
In the first part of our studies, we analyzed a novel inducible transgenic mouse model (TAU62 mice), expressing a truncated form of human wild-type tau (tau151-421, noted tau). TAU62 mice displayed axonal dysfunction and slowly progressive motor phenotype. Importantly, the neurotoxicity of tau was strongly enhanced when full-length P301S tau was co-expressed. In particular, P301SxTAU62 (abbreviated P62) double transgenic mice showed rapidly progressive, severe motor impairment, which was reversed by stopping the tau expression. Consistently, neuronal dysfunction and tau hyperphosphorylation were reversed in P62 mice when expression of tau was switched-off. These results demonstrate that tau exacerbates the toxicity of full-length tau and thereby induces severe but reversible neuronal dysfunction associated with structural changes. In parallel, we showed that induction of autophagy, using the mTORC1 inhibitor rapamycin, is sufficient to improve tau clearance in a transgenic mouse model of tauopathy (P301S mice). Rapamycin significantly delayed the progression of tau pathology in P301S mice, which was associated with a reduction in the accumulation of insoluble tau.
Together, these data provide novel insights into the pathogenesis of tauopathies. They pave new ways for novel therapeutic strategies, which can prevent the fragmentation of tau and/or promote the process of autophagy.