| Summary: | 博士 === 國立陽明大學 === 生化暨分子生物研究所 === 103 === Alzheimer's disease (AD) is one of the most common dementia. It is now believed that aggregation of β-amyloid peptide (Aβ) plays a crucial role in AD. Aβ is the major component of neuritic plaque found in the brains of patients with AD. Aβ, containing 39-42 amino acids, is a proteolysis product of β-amyloid precursor protein (AβPP). Studies have shown that membrane lipids may induce conformational changes of Aβ from α-helix into β-sheet. It has also been reported that cell membrane-like environments could promote Aβ aggregation. These suggested that the interactions between membrane lipids and Aβ might alter the structural property and conformational stability of Aβ. Currently, the interaction mechanism of Aβ with membrane lipids remains largely unknown. An understanding of the interaction mechanism may help us gain insight into the role of cell membrane in Aβ aggregation. The main purpose of this study is to characterize the interactions between Aβ and membrane lipids from the structural point of view by using nuclear magnetic resonance (NMR) spectroscopy. Previously, our lab used DHPC/DMPC (1,2-dihexanoyl-sn-glycero-3-phosphocholine/1,2-dimyristoyl-sn-glycero-3-phosphocholine) bicelles and familial Alzheimer's disease-linked A21G variant of Aβ40 (Flemish Aβ40 variant) as a model to investigate the mechanism of interaction between Aβ and membrane lipids. DMPC and DHPC are zwitterionic phoshpholipids. In this study, anionic phospholipid bicelles, DHPS/DMPS (1,2-dihexanoyl-sn-glycero-3 -phospho-L-serine /1,2-dimyristoyl-sn-glycero- 3-phospho-L-serine) bicelles, were used to mimic cell membrane. The results suggested that Aβ interacted with lipid bicelles without inducing significant change of its structural conformation and the effect of lipid charge on the interactions between Aβ and phospholipids was insignificant. Besides, the truncation mutant of Flemish Aβ40, Aβ34(A21G), in the absence and presence of DHPS/DMPS bicelles displayed no significant difference in their NMR spectral patterns, indicating that there was no significant interaction between Aβ34(A21G) and DHPS/DMPS bicelles. This finding suggested that the C-terminal residues of Aβ play an important role in the interaction between Aβ and membrane lipids. These results may provide us with information about the interaction mechanism of Aβ with cell membranes.
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