Single Molecule Studies of Early Stages of Amyloid Aggregation an Effect of pH

Abstract

The deposition of amyloid fibrils in senile plaques of the brain is the hallmark for many neurodegenerative diseases including Alzheimer's disease (AD). The normal pH in the neuron is neutral, which may decrease due to the mental depression or other environmental factors that may affect amyloid aggregation inside the brain. Moreover, liposomes in the brain are acidic. In vitro studies indicate that acidic pH accelerates amyloid aggregation but the molecular mechanism underlying this effect is unknown. In this work, we probed a Aβ(14-23) trimer and tetramer using our previously developed flexible nano array (FNA) technique to characterize the assembly of this peptide in trimers and tetramers depending on pH. Using atomic force microscopy-single molecule force spectroscopy, and fluorescence based tethered approach for probing intermolecular interactions (TAPIN) approach, we found that pH affects the pathways of oligomers assembly. If at neural pH there is primarily one assembly pathway, at acidic pH three different pathways with different stabilities were identified. Models for the assembly of Aβ(14-23) trimers and tetramers are proposed. We posit that the highly stable oligomers found at acidic pH lead to acceleration of aggregation process suggesting that acidic pH may be a risk factor in development of AD.Acknowledgements. The work was supported by NIH grants R01 GM096039 and R01GM118006 to YLL.