Inhibition of Amyloid β-Induced Lipid Membrane Permeation and Amyloid β Aggregation by K162
Copyright policy )Inhibition of Amyloid β-Induced Lipid Membrane Permeation and Amyloid β Aggregation by K162
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.
- University of California, San Francisco United States
- Lawrence Berkeley National Laboratory United States
- University of Guelph Canada
- INSTYTUT CHEMII FIZYCZNEJ POLSKIEJ AKADEMII NAUK Poland
- Cardinal Stefan Wyszyński University in Warsaw Poland
Amyloid β Aggregation, Aging, Neurodegenerative, Alzheimer's Disease, Microscopy, Atomic Force, Biochemistry, Medicinal and biomolecular chemistry, 2.1 Biological and endogenous factors, amyloid β aggregation, K 162 inhibition mechanism, Cancer, βM, Microscopy, EIS, atomic force microscopy, formation, Atomic Force, Biological Sciences, Alzheimer's disease, Lipids, atomic force, toxicity inhibition, 5.1 Pharmaceuticals, Neurological, amyloid beta aggregation, amyloid β, AFM, Electrochemical impedance spectroscopy, Alzheimer’s disease, Amyloid, β aggregation, Chemical Sciences not elsewhere classified, Biophysics, Molecular Dynamics Simulation, βOs BLM permeation, Medicinal and Biomolecular Chemistry, bilayer lipid membrane, Alzheimer Disease, membrane permeation, β toxicity inhibitors, Acquired Cognitive Impairment, Humans, Pharmacology, Amyloid beta-Peptides, MD, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), AD, Cell Biology, 540, Peptide Fragments, Brain Disorders, amyloid beta, K 162, Biochemistry and cell biology, Dementia, Biochemistry and Cell Biology, Physical Sciences not elsewhere classified, Analytical chemistry, Neuroscience
Amyloid β Aggregation, Aging, Neurodegenerative, Alzheimer's Disease, Microscopy, Atomic Force, Biochemistry, Medicinal and biomolecular chemistry, 2.1 Biological and endogenous factors, amyloid β aggregation, K 162 inhibition mechanism, Cancer, βM, Microscopy, EIS, atomic force microscopy, formation, Atomic Force, Biological Sciences, Alzheimer's disease, Lipids, atomic force, toxicity inhibition, 5.1 Pharmaceuticals, Neurological, amyloid beta aggregation, amyloid β, AFM, Electrochemical impedance spectroscopy, Alzheimer’s disease, Amyloid, β aggregation, Chemical Sciences not elsewhere classified, Biophysics, Molecular Dynamics Simulation, βOs BLM permeation, Medicinal and Biomolecular Chemistry, bilayer lipid membrane, Alzheimer Disease, membrane permeation, β toxicity inhibitors, Acquired Cognitive Impairment, Humans, Pharmacology, Amyloid beta-Peptides, MD, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), AD, Cell Biology, 540, Peptide Fragments, Brain Disorders, amyloid beta, K 162, Biochemistry and cell biology, Dementia, Biochemistry and Cell Biology, Physical Sciences not elsewhere classified, Analytical chemistry, Neuroscience
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