Characterization of Amyloid-B Interactions at the Membrane Interface: Implications for Pathogenesis. Implications for Pathogenesis.

Amyloid-beta;Alzheimer"s Disease;Membrane Permeabilization;Conformation and Oligomerization;Membrane Binding;Fluidity and Charge;Biological Chemistry;Health Sciences;Biological Chemistry

Wong, Pamela T.Xu, Zhaohu ;

University of Michigan

关键词: Amyloid-beta;    Alzheimer";    s Disease;    Membrane Permeabilization;    Conformation and Oligomerization;    Membrane Binding;    Fluidity and Charge;    Biological Chemistry;    Health Sciences;    Biological Chemistry;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/62398/ptw_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

The 40 and 42 residue amyloid-β (Aβ) peptides are major components of the proteinaceous plaques prevalent in the Alzheimer’s disease afflicted brain and have been shown to play an important role in instigating neuronal degeneration.Whereas it was previously thought that Aβ becomes cytotoxic upon forming large fibrillar aggregates, recent studies suggest that soluble intermediate sized oligomeric species cause cell death through membrane permeabilization.In this thesis we examine the interactions between Aβ40 and lipid membranes using liposomes as a model system to determine how changes in membrane composition influence the conversion of Aβ into these toxic species.Aβ40 membrane binding was monitored using fluorescence based assays with a tryptophan substituted peptide (Aβ40 [Y10W]).We extend previous observations that Aβ40 interacts preferentially with negatively charged membranes, and show that binding of nonfibrillar, low molecular weight oligomers of Aβ40 to anionic, but not neutral, membranes involves insertion of the peptide into the bilayer, as well as sequential conformational changes corresponding to the degree of oligomerization induced.Significantly, while anionic membranes in the gel, liquid crystalline, and liquid ordered phases all induce these conformational changes equally, membrane permeabilization is dramatically reduced as the fluidity of the membrane is decreased.These findings demonstrate that binding alone is not sufficient for membrane permeabilization, and that the latter is also highly dependent on the fluidity and phase of the membrane.Weconclude that binding and pore formation are two distinct steps.The differences in Aβ behavior induced by membrane composition may have significant implications on the development and progression of AD as neuronal membrane composition is altered with age.