Cholesterol is an important factor affecting the membrane insertion of beta-amyloid peptide (A beta 1-40), which may potentially inhibit the fibril formation.
beta-Amyloid peptide (A beta), a normal constituent of neuronal and non-neuronal cells, has been proven to be the major component of extracellular plaque of Alzheimer's disease. Interactions between A beta and neuronal membranes have been postulated to play an important role in the neuropathology of Alzheimer's disease. Here we show that A beta is able to insert into lipid bilayer. The membrane insertion ability of A beta is critically controlled by the ratio of cholesterol to phospholipids. In a low concentration of cholesterol A beta prefers to stay in membrane surface region mainly in a beta-sheet structure. In contrast, as the ratio of cholesterol to phospholipids rises above 30 mol%, A beta can insert spontaneously into lipid bilayer by its C terminus. During membrane insertion A beta generates about 60% alpha-helix and removes almost all beta-sheet structure. Fibril formation experiments show that such membrane insertion can reduce fibril formation. Our findings reveal a possible pathway by which A beta prevents itself from aggregation and fibril formation by membrane insertion.
Ji
Shang-Rong
SR
Department of Biological Sciences and Biotechnology, State-Key Laboratory of Biomembrane, Tsinghua University, Beijing 100084, People's Republic of China.
Wu
Yi
Y
Sui
Sen-fang
SF
D015060:1,2-Dipalmitoylphosphatidylcholine; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D002462:Cell Membrane / Q000502:physiology*; D002784:Cholesterol / Q000378:metabolism*; D002942:Circular Dichroism; D006801:Humans; D006868:Hydrolysis; D008051:Lipid Bilayers; D008563:Membrane Lipids / Q000378:metabolism; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D009474:Neurons / Q000502:physiology*; D010206:Papain; D010446:Peptide Fragments / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D016229:Amyloid beta-Peptides; D008051:Lipid Bilayers; D008563:Membrane Lipids; D010446:Peptide Fragments; D010743:Phospholipids; C078592:amyloid beta-protein (1-40); D015060:1,2-Dipalmitoylphosphatidylcholine; D002784:Cholesterol; D010206:Papain