A seeding-based neuronal model of tau aggregation for use in drug discovery

by Ines S. Amorim, Sylvie Challal, Laetitia Cistarelli, Thierry Dorval, Laurene Abjean, Manuelle Touzard, Nicolas Arbez, Arnaud Fran çois, Fany Panayi, Ross Jeggo, Erika Cecon, Atsuro Oishi, Julie Dam, Ralf Jockers, Patricia Machado Intracellular accumulation of tau protein is a hallmark of Alzheimer’s Disease and Progressive Supranuclear Palsy, as well as other neurodegenerative disorders collectively known as tauopathies. Despite our increasing understanding of the mechanisms leading to the initiation and progression of t au pathology, the field still lacks appropriate disease models to facilitate drug discovery. Here, we established a novel and modulatable seeding-based neuronal model of full-length 4R tau accumulation using humanized mouse cortical neurons and seeds from P301S human tau transgenic animals. The mode l shows specific and consistent formation of intraneuronal insoluble full-length 4R tau inclusions, which are positive for known markers of tau pathology (AT8, PHF-1, MC-1), and creates seeding competent tau. The formation of new inclusions can be prevented by treatment with tau siRNA, providing a r obust internal control for use in qualifying the assessment of potential therapeutic candidates aimed at reducing the intracellular pool of tau. In addition, the experimental set up and data analysis techniques used provide consistent results in larger-scale designs that required multiple rounds of independent experiments, making this is a versatile and valuable...
Source: PLoS One - Category: Biomedical Science Authors: Source Type: research