A NOVEL INDUCIBLE MODEL TO STUDY TAUOPATHY IN ALZHEIMER’S DISEASE APPLICABLE TO BOTH, MOUSE AND HUMAN NEURAL TISSUES

Tauopathies are a heterogeneous group of neurodegenerative diseases characterized by the abnormal accumulation, hyperphosphorylation, and aggregation of TAU protein. Despite the development of different transgenic animal models, research progress to understand its pathological mechanisms and identification of new therapeutic targets is still limited. Therefore, there is an urgent need for the development of novel models for these neurodegenerative disorders that may combine both in vitro and in vivo approaches to recapitulate better the complex pathophysiology underlying these forms of dementia.
In this study, we used an inducible model based on an adeno-associated viral (AAV) vector expressing human hTAUP301L to be employed in mice, human embryonic stem cells-derived neurons and organotypic human brain slices.
In vivo, 6-month-old wild-type mice received bilateral hippocampal injections of AAV-hTAUP301L. Behavioural phenotyping revealed significant impairments in declarative memory, locomotion and depressive-like behaviours. In parallel, to further validate this tool, human embryonic stem cells differentiated into neurons were also transduced, showing robust tau-induced neurotoxicity and neuronal death. Finally, adult human brain organotypic slices were transduced with AAV-hTAUP301L, resulting in robust p-tau (AT8) expression and evidence of spreading into the surrounding parenchyma by 16 days post-infection. This human-based systems offers a novel translational platform to identify and test pharmacological targets aimed at reducing TAU aggregates.
In summary, our results suggest that AAV-hTAUP301L is an innovative and versatile tool for developing inducible translational models of tauopathies across different biological systems.