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

Abstract

Alzheimer's disease (AD) is characterized by progressive neurodegeneration associated with amyloid β (Aβ) peptide aggregation. The aggregation of Aβ monomers (AβMs) leads to the formation of Aβ oligomers (AβOs), the neurotoxic Aβ form, capable of permeating the cell membrane. Here, we investigated the effect of a fluorene-based active drug candidate, named K162, on both Aβ aggregation and AβO 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 AβOs-induced BLM permeation, thus preserving BLM integrity. In the presence of K162, only shallow defects on the BLM surface were formed. Apparently, K162 modifies Aβ aggregation by bypassing the formation of toxic AβOs, and only nontoxic AβMs, dimers (AβDs), and fibrils (AβFs) are produced. Unlike other Aβ toxicity inhibitors, K162 preserves neurologically beneficial AβMs. This unique K162 inhibition mechanism provides an alternative AD therapeutic strategy that could be explored in the future.

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

“…This phenomenon is affected by specific lipids including cholesterol, sphingomyelin, and gangliosides [717,718]: lipid types typically present in the outer leaflet of the cell membrane. Amyloid fibers at a membrane surface have thus been frequently studied using MD simulations, e.g., [719][720][721][722][723][724][725][726][727][728][729][730], however, a surprisingly small fraction of this work has been performed in the context of drug design [731,732]. Khondker et al, proposed designing drugs with a mode of action that involved modulating membrane properties to affect the aggregation of amyloid-β25-35 at the bilayer surface [229].…”

Potential Anti-Alzheimer Agents from Guanidinyl Tryptophan Derivatives with Activities of Membrane Adhesion and Conformational Transition Inhibitions

“…Those results are consistent with the present findings. For example, the study of Mrdenovic et al [ 4 ] into the fluorene-based compound K162 and their electrochemical impedance spectroscopy results showed that cell membrane integrity was preserved when both Aβ oligomers and K162 were presented. No pore formed in the membrane, which was confirmed by atomic force microscopy imaging.…”

“…Furthermore, the disruption of the cell membrane may result in the internalization of Aβ into the cytosol. The in vitro study by Mrdenovic et al [ 4 ] showed that the aggregation of the Aβ monomers can result in the formation of Aβ oligomers, which is the neurotoxic form. This neurotoxic protein is able to permeate the cell membrane.…”

A Ratiometric Fluorescent Conjugated Oligomer for Amyloid β Recognition, Aggregation Inhibition, and Detoxification

“…[ 9–11 ] However, very few ratiometric fluorescent probes for Aβ recognition have been reported. [ 12–15 ] On the other hand, a variety of approaches to inhibit Aβ aggregation have been developed, [ 16 ] such as small molecules, [ 17–22 ] polymers, [ 23–25 ] peptides, [ 26–27 ] nanomaterials, [ 28–34 ] nanocomposites, [ 35–37 ] which functioned mainly by noncovalent interactions, including electrostatic interactions, π‐π stacking, hydrogen bonding, and hydrophobic interactions. These interactions are unstable and sensitive to interferences, such as temperature or pH.…”