The Structure of Tau Paired Helical Filaments

Negative stain transmission electron microscopy images of filamentous structures formed from truncated tau monomers. Filament formation was induced by heparin. Arrows mark the twist repeats.

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Microtubule-associated protein tau forms insoluble filamentous aggregates known as paired helical filaments. These are a common feature of the tauopathies. In Alzheimer's disease they form neurofibrally tangles within neurons.

In this project we study various tau fibrils assembled in vitro, either de novo or by the addtion of pre-formed fibril seeds. The structures obtained by high-resolution transmission electron microscopy (TEM) and helical image processing will be related to the various tauopathies, helping to understand their typical pathologies.

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Neurodegenerative diseases are a fast-growing threat to public health, especially for the elderly. Among the most common disorders are tauopathies such as Alzheimer’s disease (AD) and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Tauopathies are defined by abnormal filamentous assemblies of tau protein in neurons. The filaments show prion-like spreading behavior and assemble from tau 'seeds' with distinct self-replicating structural conformations (known as 'tau strains').  These strains are associated with different diseases. The structures of the various seeds and fibrils are still unknown and could provide vital information on disease mechanisms and disease progression. 

In this project, we express recombinant human tau protein in E. coli and purify it for structural studies. The formation of filaments is then induced in vitro, either with molecular agents such as heparin or by the addition of short pre-formed filaments that act as seeds.

Imaging by cryo-electron microscopy and helical image processing will be used to obtain a three dimensional reconstruction of the filament. This promises to give new insights into the pathological role of fibrils in tau pathologies. Furthermore, distinct structures from different tauopathies will be compared in order to gain a mechanical understanding of tau pathology in neurodegenerative diseases, thus paving the way for new therapeutic approaches.