Beta Sheets, Mutations, and Orthomolecular Inhibitors, Oh My: A Comparison of Beta-Sheet Production Across Mutants and the Effects of B17 on Inhibition of Fibril Formation

Abstract

Beta-sheet fibril deposits are a crucial hallmark of Alzheimer's disease. Characterized by accumulations of highly toxic beta-sheet structures, fibril tangles disrupt synaptic function causing impaired memory. Amassing toxicity results in neuronal degradation and ultimately complete brain death. Beta-amyloid research focuses on one region of the 40-42 amino acid length beta-amyloid known as “KLVFFA”; this region, from residues 16-21, is believed to be the single, shortest, and most important contributor to beta-sheet formation. However, these theories overlook the crucial portion of the peptide, at residues 23-28, containing an ionic interaction inducing a hair pin turn. This potential rate limiting step in the folding of beta-amyloid provides new insight into the pathogenesis of Alzheimer's disease. Cleavage at residues 22 and 35 excludes the effect of “KLVFFA” and limits secondary folding interactions of the N-terminus after 35. Spectral analysis of the Wild Type WT Aβ22-35 lays ground work for various single point mutations within the shorter fragment. Aβ-E22G and Aβ-D23N, also known as the Arctic mutation and Iowa mutation respectively, are characterized by faster accumulation of amyloid fibrils. Beta-sheet production occurs rapidly, but can be observed by the implementation of ATR-IR spectroscopy focusing on signature chemical shifts in the amide one and amide two regions within the peptide. Second, pentamaric binding of multiple secondary beta structures to Congo-Red dye solution confirms the production of beta-sheets via UV/Vis. Moreover, time dependant TEM imaging of the WT revealed the presence of fibrils, demonstrating the importance of studying this shorter fragment. Suppression of fibril formation by the addition of concentrated orthomolecular compounds could yield therapeutic techniques or possibly even a cure for Alzheimer's disease.