Simulation of the Oligomerization Pathway for Different Alloforms of the Amyloid Beta Protein Related to Alzheimer's Disease

Abstract

Numerous recent experimental studies suggest that oligomers of amyloid beta protein (Aβ) are the principal neurotoxic agents in Alzheimer's disease. In fact, these oligomers interact with receptors, metal-ions, cell membrane and synapses causing neuronal dysfunction or even death. They also have the ability to form pores disrupting neurons homeostasis. Details of these mechanisms remain largely unknown at the molecular level and clearly structural information on these oligomers would provide crucial breakthrough in the understanding of their neurotoxicity. Yet, it is difficult to isolate specific Aβ oligomers and characterize their morphologies experimentally since they are prone to aggregation and they exist in equilibrium with monomers, fibrils and other orders of oligomers. Thus, to complement experimental results, numerical simulations are used to get insights on the molecular mechanisms of Aβ aggregation. We present our results on the amyloid beta monomer and dimer using an efficient simulation protocol that is introduced in details. We study specifically three alloforms of Aβ: Aβ1-40, which is less prone to aggregation; Aβ1-42, which is more toxic; and Aβ1-40(D23N), which is a single point mutation causing early onset Alzheimer's disease. Our results, which are in good agreement with experiment and help understand a number of observations, show that small variation in the sequence results in important morphological changes related to the different oligomerization pathways of these alloforms.