期刊
JOURNAL OF MOLECULAR BIOLOGY
卷 430, 期 7, 页码 919-934出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2018.01.008
关键词
Alzheimer's disease; A beta; HSA; ion channels; oligomers
资金
- BBSRC [BB/M023877/1]
- Queen Mary Life Sciences Initiative
- BBSRC [BB/M023877/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/M023877/1, 978364] Funding Source: researchfish
Central to Alzheimer's disease (AD) pathology is the assembly of monomeric amyloid-beta peptide (A beta) into oligomers and fibers. The most abundant protein in the blood plasma and cerebrospinal fluid is human serum albumin. Albumin can bind to A beta and is capable of inhibiting the fibrillization of A beta at physiological (mu M) concentrations. The ability of albumin to bind A beta has recently been exploited in a phase II clinical trial, which showed a reduction in cognitive decline in AD patients undergoing albumin-plasma exchange. Here we explore the equilibrium between A beta monomer, oligomer and fiber in the presence of albumin. Using transmission electron microscopy and thioflavin-T fluorescent dye, we have shown that albumin traps A beta as oligomers, 9 nm in diameter. We show that albumin-trapped A beta oligomeric assemblies are not capable of forming ion channels, which suggests a mechanism by which albumin is protective in A beta-exposed neuronal cells. In vivo albumin binds a variety of endogenous and therapeutic exogenous hydrophobic molecules, including cholesterol, fatty acids and warfarin. We show that these molecules bind to albumin and suppress its ability to inhibit A beta fiber formation. The interplay between A beta, albumin and endogenous hydrophobic molecules impacts A beta assembly; thus, changes in cholesterol and fatty acid levels in vivo may impact A beta fibrillization, by altering the capacity of albumin to bind A beta. These observations are particularly intriguing given that high cholesterol or fatty acid diets are well-established risk factors for late-onset AD. (C) 2018 Elsevier Ltd. All rights reserved.
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