Molecular Mechanism of Zinc-Dependent Oligomerization of Alzheimer’s Amyloid-β with Taiwan (D7H) Mutation

Amyloid-β (Aβ) is a peptide formed by 39–43 amino acids, heterogenous the length of its C-terminus. Aβ constitutes subnanomolar monomeric component human biological fluids; however, in sporadic variants Alzheimer’s disease (AD), it forms soluble neurotoxic oligomers and accumulates as insoluble extracellular polymeric aggregates (amyloid plaques) brain tissues. The plaque formation controlled zinc ions; therefore, abnormal interactions between ions seem to take part triggering AD. amyloid plaques contain various isoforms, among which most common with an isoaspartate position 7 (isoD7). spontaneous conversion D7 isoD7 associated aging. molecules (isoD7-Aβ) easily undergo zinc-dependent oligomerization, upon administration transgenic animals (mice, nematodes) used for AD modeling, act seeds pathological aggregation Aβ. zinc-bound homo- hetero-oligomers participation isoD7-Aβ based on rigidly structured segment 11-EVHH-14, located metal binding domain (Aβ16). Some hereditary are familial mutations within domain. Among these, susceptible oligomerization Taiwan (D7H) mutation (D7H-Aβ). In this study, D7H-Aβ (D7H-Aβ16) has been model establish molecular mechanism zinc-induced through turbidimetry, dynamic light scattering, isothermal titration calorimetry, mass spectrometry, computer modelling. Additionally, modeling data showed that molecule D7H-Aβ, well combination two molecules, renders stable heterotrimer. trimers held together intermolecular interfaces via ions, primary 11-EVHH-14 sites interacting trimer subunits. summary, obtained results confirm role region structure function determinant all known species (including chemically modified isoforms AD-associated mutants) point at potent target drugs aimed stop both