Cavallini, Annalisa; (2018) Development and characterization of cell models of tau aggregation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Abnormal folding and hyperphosporylation of tau protein leads to the generation of paired helical filaments (PHFs) and neurofibrillary tangles (NFTs), a key neuropathological hallmark of Alzheimer’s disease and other tauopathies. Cellular models able to recapitulate tau pathology are useful for understanding disease mechanisms and screening and profiling compounds that interfere with tau aggregation. We have established a HEK T-REx cell culture model where the inducible expression of mutant tau, accompanied by the introduction of aggregated mutant tau extracted from transgenic mouse brain, leads to endogenous tau aggregation and filament assembly, suggesting a seeding process as a likely mechanism underlying NFT formation. We found that substantial aggregation of soluble tau into Triton X-100-insoluble tau can be induced by spontaneous uptake of mutant tau aggregates, which are internalised through an endocytic mechanism that is temperature-, time- and ATP-dependent, can be potentiated by transfection reagents and impaired by pharmacological agents inhibiting macropinocytosis, suggesting a potential mechanism for the propagation of tau pathology in tauopathy brains. We also found that seed-competent tau species are sarkosly-insoluble, tagged by AT8 and MC1 antibodies, and are present in conditioned media from seeded cells. Finally, we established a more physiologically relevant model of seeded tau aggregation in rodent neurons. In summary, our study establishes cell-based tauopathy models that not only provide mechanistic insights into the pathogenesis of tau aggregation, but also offer a robust system for identifying therapeutic strategies to prevent propagation and spreading of tau pathology.

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