Cross-Seeding Interaction Between Amyloid β and Tau Protein can Enhance Aggregation

Background: The two pathological hallmarks associated with Alzheimer’s disease (AD) include the accumulation of senile plaques and the generation of neurofibrillary tangles. Although it is a known fact that both amyloid beta (Aβ) and Tau exist together in mitochondria, to date, there is no reasonable explanation for the Aβ and Tau interaction in particular. Objective: The cross-seeding interactions between Aβ and Tau were studied using the potential of mean force (PMF) analysis. Methods: The Aβ- Aβ homo-dimer; Tau-Tau homo-dimer and Aβ-Tau hetero-dimer were constructed using molecular docking tools. We have used molecular dynamics (MD) simulation with the umbrella sampling methodology to examine the cross-sequence interactions between homo-dimers and the hetero- dimer by computing PMF. Results: We observed the global minimum and energy barrier to be quite higher for both the homodimers relative to the hetero-dimer, thus indicating that Aβ (25-35) has a high affinity to form dimer complex with Tau (273-284) monomer. We also observed a relatively higher range of interacting residues and interface area between the monomeric units in hetero-dimer (Aβ-Tau) the homo-dimer (Aβ- Aβ) and (Tau-Tau) showed a less number of the same. Conclusion: From the results we may therefore conclude that Aβ fragments can form complexes with the Tau monomers which consequently advance to form aggregates. This aggregation may be favored by interactions between the hydrophobic residues and charged residues present in both the fragments.