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The folding and aggregation of the tau protein in Alzheimer’s disease

Alzheimer’s disease is characterised by the formation of toxic oligomeric aggregates of intrinsically disordered Tau and amyloid β proteins. In the case of Tau, this is triggered by aberrant post-translational modifications, such as hyperphosphorylation and acetylation, which lead to an increased tendency for self-aggregation through a molecular mechanism that is poorly understood. The essential amyloid core motifs responsible for the aggregation of the Tau protein are hexapeptide sequences known as PHF6* and PHF6 that are essential for the initiation of aggregation. Understanding the underlying molecular mechanisms of the misfolding and aggregation of the Tau protein is essential for the rational design of small molecular inhibitors of this deleterious process. Molecular dynamics simulations will be used to obtained a detailed, atomistic-level description of the folding and aggregation pathways of different regions of the Tau protein. The effects of phosphorylation and/or acetylation on the structure of key regions of the Tau protein will be predicted and contrasted with experimental data (nuclear magnetic resonance and circular dichroism measurements). The effect of phosphorylation on the ability of aggregation and fibrillation of PHF binding motifs and microtubule-binding repeat domains will be investigated.

Key interactions that stabilise a turn region upon phosphorylation of Thr 205
Key interactions that stabilise a turn region upon phosphorylation of Thr 205, giving rise to the well-known AT8 epitope in the Tau protein. Taken from Gandhi et al. (2015) Angew. Chem. Int. Ed. 54, 6819.