Membrane Interaction Of Amyloid-Beta Peptide Induces Spontaneous Membrane Invagination

One of the pathological hallmarks of Alzheimer's disease (AD) is extracellular plaques, in which the 42aa Amyloid beta peptide (Aβ 1-42) is the main component. Aβ 1-42 is produced at cholesterol-rich regions of neuronal membranes by endoproteolysis of the parental amyloid precursor protein and is secreted into the extracellular space. Although Aβ 1-42 accumulates extracellularly, neurons internalize the Aβ 1-42 peptide which could contribute to disease progression and which may be the first step to both cytotoxicity and propagation of misfolded Aβ between cells. Interaction with membrane bilayer is likely the first step in the molecular mechanism of neuronal Aβ 1-42 uptake. Therefore, we studied interaction of Aβ 1-42 with the lipid bilayer in a giant unilamellar vesicles (GUVs) model system. We found that the Aβ 1-42 bound to the lipid bilayer and, after a lag phase induced invagination of the membrane into small vesicular structures. Only early oligomeric structures of Aβ and stabilized the negative curvature of membrane, whereas both monomeric and fibrillar forms of the peptide were unable to induce or sustain membrane invagination. Our results suggest that Aβ may facilitate vesicle formation in lipid bilayer membranes, which may be a factor in cellular Aβ internalization but may also hint at a possible physiological function of the Aβ peptide at the synaptic membrane.