(570d) N-Terminal Hypothesis for Alzheimer’s Disease: Analyzing Dimers of a ? peptide and its Protective and Causative Mutants

The amyloid (Aβ peptide) hypothesis dominates the pathogenesis of Alzheimer’s Disease (AD), yet it is still controversial. This is due to a lack of a mechanistic path from the cleavage products of the amyloid precursor protein (APP) such as soluble Aβ monomer and soluble molecular fragmentsand to their deleterious effects on synaptic form and function. From a review of previously published work including aggregation kinetics and structural morphology, Aβ_1-42 clearance, molecular simulations, long-term potentiation measurements with inhibition binding, and the binding of a commercial monoclonal antibody, aducanumab, we hypothesize that the N-terminal domains of neurotoxic Aβ oligomers are implicated in causing the disease. We call this the “N-Terminal Hypothesis for AD”. In order to understand the behavior of the N-terminus, we use brute force and replicate exchange molecular simulations guided by the recently reported NMR fibril structure of Aβ peptide and conduct kinetic aggregation and long-term potentiation measurements.

The structure of homozygous and heterozygous dimers of wild-type Aβ_1-42, and its causative (A2V) and protective (A2T) variants are analyzed. To study the role of N-terminus in the interactions between Aβ dimers, we constrain the central hydrophobic region and C-terminus to the known structure of Aβ fibers, while leaving the N-terminus free and examine the structural differences between these dimers. Furthermore, we performed unconstrained simulations of Aβ dimers to understand their association and the resulting structures. To analyze these dimers we examined the number of contacts and distances between the N-termini, and contact (2D heat) maps of their conformational landscape. Aggregation kinetics and long term potentiation of the three variants are also measured and compared in the presence and absence of monoclonal antibody, bapineuzumab, which targets N-terminal residues 1-5 of Aβ with high affinity.