Inhibition of Amyloid ß-Induced Lipid Membrane Permeation and Amyloid ß Aggregation by K162.
ACS Chem Neurosci
; 12(3): 531-541, 2021 02 03.
Article
de En
| MEDLINE
| ID: mdl-33478212
ABSTRACT
Alzheimer's disease (AD) is characterized by progressive neurodegeneration associated with amyloid ß (Aß) peptide aggregation. The aggregation of Aß monomers (AßMs) leads to the formation of Aß oligomers (AßOs), the neurotoxic Aß form, capable of permeating the cell membrane. Here, we investigated the effect of a fluorene-based active drug candidate, named K162, on both Aß aggregation and AßO 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 AßOs-induced BLM permeation, thus preserving BLM integrity. In the presence of K162, only shallow defects on the BLM surface were formed. Apparently, K162 modifies Aß aggregation by bypassing the formation of toxic AßOs, and only nontoxic AßMs, dimers (AßDs), and fibrils (AßFs) are produced. Unlike other Aß toxicity inhibitors, K162 preserves neurologically beneficial AßMs. This unique K162 inhibition mechanism provides an alternative AD therapeutic strategy that could be explored in the future.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Peptides bêta-amyloïdes
/
Maladie d'Alzheimer
Limites:
Humans
Langue:
En
Journal:
ACS Chem Neurosci
Année:
2021
Type de document:
Article
Pays d'affiliation:
Pologne