Inhibition of Amyloid β-Induced Lipid Membrane Permeation and Amyloid β Aggregation by K162
| Autor: | Piotr Pieta, Robert Nowakowski, Piotr Zarzycki, Izabela S. Pieta, Marta Majewska, Dusan Mrdenovic, Jacek Lipkowski, Wlodzimierz Kutner |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Amyloid
Physiology Cognitive Neuroscience Peptide Molecular Dynamics Simulation Fibril Microscopy Atomic Force Biochemistry Cell membrane 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Alzheimer Disease membrane permeation medicine Humans amyloid β aggregation Lipid bilayer 030304 developmental biology chemistry.chemical_classification 0303 health sciences atomic force microscopy Amyloid beta-Peptides Chemistry Bilayer Cell Biology General Medicine Permeation Lipids Peptide Fragments toxicity inhibition medicine.anatomical_structure Monomer Toxicity Biophysics amyloid β Alzheimer’s disease 030217 neurology & neurosurgery Research Article |
| Zdroj: | ACS Chemical Neuroscience |
| ISSN: | 1948-7193 |
| DOI: | 10.1021/acschemneuro.0c00754 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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