Inhibition of Amyloid ?-Induced Lipid Membrane Permeation and Amyloid ? Aggregation by K162.

ABSTRACT: Alzheimer's disease (AD) is characterized by progressive neurodegeneration associated with amyloid ? (A?) peptide aggregation. The aggregation of A? monomers (A?Ms) leads to the formation of A? oligomers (A?Os), the neurotoxic A? form, capable of permeating the cell membrane. Here, we investigated the effect of a fluorene-based active drug candidate, named K162, on both A? aggregation and A?O toxicity toward the bilayer lipid membrane (BLM). Electrochemical impedance spectroscopy (EIS), atomic force microscopy (AFM), and molecular dynamics (MD) were employed to show that K162 inhibits A?Os-induced BLM permeation, thus preserving BLM integrity. In the presence of K162, only shallow defects on the BLM surface were formed. Apparently, K162 modifies A? aggregation by bypassing the formation of toxic A?Os, and only nontoxic A?Ms, dimers (A?Ds), and fibrils (A?Fs) are produced. Unlike other A? toxicity inhibitors, K162 preserves neurologically beneficial A?Ms. This unique K162 inhibition mechanism provides an alternative AD therapeutic strategy that could be explored in the future.

SUBMITTER: Mrdenovic D 

PROVIDER: S-EPMC7877724 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature