Alzheimer’s disease (AD), a neurodegenerative disease associated with impaired neural function and neuronal apoptosis, is a leading cause of death in those 65 and older across the globe. It is estimated that over 50 million people are affected worldwide, with this number climbing each year. Familial Alzheimer’s disease (fAD) is a rare, genetically inherited form of AD, denoted by unique gene point-mutations in the amyloid precursor protein (APP). Both fAD and AD pathology are distinguished by the misfolding and subsequent aggregation of the amyloid-β protein (Aβ), derived from the proteolytic cleavage of the APP. Genetically inherited APP mutations, frequently localized in the Aβ coding region, are known to cause significant conformational effects on Aβ. These structural alterations often alter protein function and interaction, subsequently affecting Aβ pathogenicity. The alanine-to-valine amino acid mutation at the second residue of Aβ-42, also referred to as A2V, is a prominent fAD mutation. Interestingly, homozygous A2V leads to early-onset AD, effectively aggravating FAD progression; however, in its heterozygous state, this mutation protects against AD. Utilizing Discrete Molecular Dynamics, Replica Exchange Simulations were run on both monomer and dimer models, allowing for the detailed observation of these homozygous and heterozygous conditions. Through the analysis of interfacial interactions and alterations of kinetic dynamics, this study aims to identify conformational distinctions between these two states that provide insight into the divergent pathogenic outcomes of the A2V mutation.
Hayes et al. (Sun,) studied this question.