1-palmitoyl-2-oleoylphosphatidylcholine and Neurodegenerative-Diseases

Alzheimer's disease (AD) is a neurodegenerative disease that results in memory loss and the impairment of cognitive skills. Several mechanisms of AD's pathogenesis were proposed, such as the progressive accumulation of amyloid-β (Aβ) and τ pathology. Nevertheless, the exact neurodegenerative mechanism of the Aβ remains complex and not fully understood. This paper proposes an alternative hypothesis of the mechanism based on maintaining the neuron membrane's mechanical balance. The incorporation of Aβ decreases the lipid membrane's elastic properties, which eventually leads to the impairment of membrane clustering, disruption of mechanical wave propagation, and change in gamma oscillations. The first two disrupt the neuron's ability to function correctly while the last one decreases sensory encoding and perception enabling. To begin discussing this mechanical-balance hypothesis, we measured the effect of two selected peptides, Aβ-40 and Aβ-42, as well as their fluorescently labeled modification, on membrane mechanical properties. The decrease of bending rigidity, consistent for all investigated peptides, was observed using molecular dynamic studies and experimental flicker-noise techniques. Additionally, wave propagation was investigated with molecular dynamic studies in membranes with and without incorporated neurodegenerative peptides. A change in membrane behavior was observed in the membrane system with incorporated Aβ.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Brain; Cell Membrane; Humans; Lipid Bilayers; Membrane Lipids; Membrane Potentials; Microscopy, Confocal; Molecular Dynamics Simulation; Neurodegenerative Diseases; Neurons; Peptide Fragments; Phosphatidylcholines

Although its function is unknown, alpha-synuclein is widely distributed in neural tissue and is the major component in the pathological aggregates found in patients with Parkinson's disease, Alzheimer's disease, Down's syndrome, and multiple system atrophy. In this report, we have quantified the binding alpha-synucleins to lipid membranes. In contrast to previous studies, we find, using real time equilibrium fluorescence methods, that alpha-synuclein binds strongly to large, unilamellar vesicles with either anionic or zwitterionic headgroups. Membrane binding is also strong for beta-synuclein, phosphorylated alpha-synuclein, and a synuclein mutant that is associated with familial Parkinson's disease. In solution at less than 400 nM, synuclein has a tendency to undergo concentration-dependent oligomerization as determined by changes in intrinsic fluorescence and fluorescence resonance energy transfer. Above this concentration, the protein begins to aggregate into structures visible by light scattering. Although membrane binding does not affect the secondary structure of alpha-synuclein, it greatly inhibits the ability of this protein to self-associate. Taken together, our results indicate that pathological conditions may be associated with a disruption in synuclein-membrane interactions.

Topics: alpha-Synuclein; beta-Synuclein; Blotting, Western; Cell Membrane; Circular Dichroism; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Escherichia coli; Humans; Hydrogen-Ion Concentration; Lipids; Nerve Tissue Proteins; Neurodegenerative Diseases; Phosphatidylcholines; Phosphatidylethanolamines; Phosphorylation; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary; Silver Staining; Spectrometry, Fluorescence; Synucleins