cis and trans isomers of phospho-tau proteins differently affect amyloid aggregation.

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The co-localization of phospho-tau proteins (p-tau) and amyloid beta (Aβ) or alpha-synuclein (α-Syn) aggregates and their combined pathological impacts have been recognized in the brains of both human and animal models of Alzheimer's disease (AD) and Parkinson's disease (PD). The fibrillation of amyloidogenic proteins is a dynamic process that can be affected by the presence of other proteins and therefore, it's essential to reveal how the cross-interaction between Aβ or α-Syn with p-tau affects their amyloidogenesis. Using simulation studies, we showed that cis and trans conformations of phosphorylated tau (phosphorylated at Thr231) show different affinities to Aβ and α-Syn. Trans p-tau showed more favorable and stronger interaction with Aβ and α-Syn and accelerated their aggregation. Consistently, the experimental approaches demonstrated that trans p-tau considerably enhances the fibrillation of both Aβ (from ∼7 h to ∼30 min) and α-Syn (from ∼10 h to ∼1 h) in a concentration-dependent manner, whereas cis p-tau, a neurotoxic isomer and early driver of tauopathy, exhibited a less pronounced acceleratory effect on amyloid aggregation (from 7 h to 5 h for Aβ and from 7 h to 5 h for α-Syn).

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