Establishing a validated molecular target that slows cognitive decline caused by Alzheimer’s disease (AD) remains an unmet challenge. Compelling evidence links brain aggregates of the amyloid-β peptide (Aβ) to synapse loss and AD-related dementia, yet without exception, all candidate therapeutics have failed to slow cognitive impairment in large double-blind placebo-controlled clinical trials despite reducing Aβ in the brain. Thus, academic research laboratories that focus on uncovering biochemical mechanisms that underlie AD are likely to illuminate novel targets for drug discovery. We hypothesized that specific Aβ oligomeric (AβO) quaternary structures, rather than their dispersity, initiate synaptic decline. Thus, neutralizing their toxicity pharmacologically may effectively slow dementia progression. Unfortunately, AβOs form structurally diverse assemblies at low levels in the brain and are unstable outside of their native environment, impeding the characterization of a target for drug discovery efforts. To identify pathogenic AβO structural isoforms that can be useful targets in small molecule library screening, we prepared homogenous AβO quaternary structures using recombinant AβOs derived from monomeric Aβ(M1–40). Aβ(M1–40) oligomers were kinetically trapped using photo-oxidative cross-linking and purified by gel filtration chromatography, enabling the isolation of homogenous assemblies with uniform dispersities and morphologies. Compared to cross-linked AβOs derived from synthetic wild-type Aβ40, Aβ(M1–40) oligomeric states displayed more variable dispersities and morphologies. To establish structure-function relationships, structural elements were further characterized spectroscopically and by their influence on viability when administered to neuronal cell lines. AβO isoforms present in minority quantities were significantly more toxic than those formed at higher concentrations under our assembly conditions. These results suggest that drug candidates may reduce AβO levels significantly, but fail to clear disease-relevant oligomers present at low concentrations. Future efforts using homogenous AβO toxicants as targets in high-throughput screening campaigns are currently underway with the goal of identifying synthetic molecules capable of neutralizing synaptic toxicity caused by native AβOs. Once these toxic AβOs can be detoxified during early stages of AD pathogenesis, then therapeutic intervention will likely be most effective.

Identification of toxic amyloid-beta oligomer quaternary structures as novel drug discovery targets to treat Alzheimer's disease-related dementia

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.