Biochemical and biophysical characterization of conformationally distinct tau protein species and their relationship with dysfunction in two models of tauopathy

Abstract

Abnormal aggregation of protein tau and subsequent neuronal dysfunction seems to be key pathological features in Alzheimer's disease and other related disorders, collectively referred to as tauopathies. It has been suggested that tau oligomers are important players in a process that precedes degeneration. However, the nature of tau aggregates and their relationship with toxicity is not well understood. The data described in this work have contributed to this research by exploring the tau species that might contribute to dysfunction at the onset of the disease and the tau species that might contribute to degeneration at the advanced stage of the disease.
To initially investigate the tau-mediated phenotypes and characterize their onset and progression, the shortest htau isoform with the P301S mutation was expressed in mouse and two different htau isoforms were expressed in Drosophila. In both models, the expression of tau causes a phenotype and this is manifested in the early and advanced stages of the disease. In Drosophila, tau expression caused reduced lifespan and deficits in climbing ability. These are two established tau phenotypes in this model and have been used as a readout to assess dysfunction due to the expression of tau in the nervous system. In the rodent model, tau expression caused locomotor impairment.
To investigate which tau species might be present and related to the appearance and progression of the observed phenotype, tau species were characterized using a number of biochemical and biophysical techniques. In both models, the earliest pathological feature was observed to be accompanied by species that resemble oligomers with altered conformation. Larger tau species (pre-NFT) with high β-structure are formed at late stages and might be potentially involved in degeneration.
In a Drosophila model expressing htau2N4R, treatment with tau aggregation inhibitor (RI-AG03) partially rescues the phenotype and reduces tau aggregation. This further confirms that aggregation is critical for the onset and progression of the disease. Further research of the pathogenic tau species responsible for the onset of disease has the potential to lead to early diagnostic markers and therapeutic targets for tauopathies.

More information

Identifiers

ORCID for Sumeet Mahajan: orcid.org/0000-0001-8923-6666

Catalogue record

Export record