Deciphering the Roles of the Key Oligomerization Domains in Amyloid‐β to Design Amyloid Aggregation Inhibitors

Abstract

AbstractBackgroundProtein folding issues are significant difficulties since they are linked to various diseases, including dementia. Fibrillar amyloid aggregates composed of misfolded proteins are pathological features of several neurodegenerative diseases. Numerous attempts have been made to treat neurodegenerative diseases by focusing on amyloid aggregates of pathologically disordered proteins. The first Alzheimer’s disease (AD) curative drug was introduced as a consequence of attempts to combat the most frequent kind of dementia. Even though antibody strategies reduce clinical deterioration in mild cognitive disease, alternate techniques must be developed over a single approach (i.e., antibody treatment). Recent studies have attempted to rationally design candidate drugs to improve existing therapeutic approaches or suppress the fibrillar amyloid aggregation process altogether. Prompted by previous findings, we rationally designed amyloid‐β (1‐42) point mutants to inhibit amyloid aggregation.MethodWe investigated the structural ensembles of the monomers using small‐angle X‐ray scattering. In addition, we performed hydrogen‐deuterium exchange mass spectrometry (MS) and ion mobility MS to elucidate the molecular principles governing Aβ42‐inhibitor interactions. We also used microsecond‐scale molecular dynamics simulations to investigate the structures and interactions, and combined them with electron transfer dissociation MS analysis to tackle challenges in identifying the multiple binding sites of intrinsically disordered protein complexes.ResultSpecifically designed mutations disrupt not only amyloid aggregation but reduce its cytotoxicity. Furthermore, we proposed minimal mutation sites to control amyloid‐β (1‐42) self‐assembly behavior. We are now determining the key domains of amyloid‐β (1‐42) that facilitate its self‐assembly to design aggregation inhibitors as potential therapeutic agents. We identified three critical hydrophobic domains (17LVF19, 32IGL34, and 41IA42) on amyloid‐β (1‐42) and investigated their role in the protein’s self‐assembly process. Our results suggest that interchain interactions in the central hydrophobic region (17LVF19) of amyloid‐β (1‐42) are essential for fibrillar aggregation and that their interaction with other domains is related to the accessibility of the central hydrophobic region for initiating the pathological cascade. Our findings shed light on the mechanisms underlying amyloid‐β (1‐42) self‐assembly and reveal key structural domains that aid in this process.ConclusionOur findings can be used to improve the rational design of amyloid‐β (1‐42) aggregation inhibitors in the future.