期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2009
卷号：106
期号：12
页码：4653-4658
DOI：10.1073/pnas.0901085106
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Alzheimer's disease is a neurodegenerative disorder characterized by the accumulation of amyloid plaques in the brain. This amyloid primarily contains amyloid-{beta} (A{beta}), a 39- to 43-aa peptide derived from the proteolytic cleavage of the endogenous amyloid precursor protein. The 42-residue-length A{beta} peptide (A{beta}1-42), the most abundant A{beta} peptide found in plaques, has a much greater propensity to self-aggregate into fibrils than the other peptides and is believed to be more pathogenic. Synthetic human A{beta}1-42 peptides self-aggregate into stable but poorly-ordered helical filaments. We determined their structure to {approx}10-A resolution by using cryoEM and the iterative real-space reconstruction method. This structure reveals 2 protofilaments winding around a hollow core. Previous hairpin-like NMR models for A{beta}17-42 fit well in the cryoEM density map and reveal that the juxtaposed protofilaments are joined via the N terminus of the peptide from 1 protofilament connecting to the loop region of the peptide in the opposite protofilament. This model of mature A{beta}1-42 fibrils is markedly different from previous cryoEM models of A{beta}1-40 fibrils. In our model, the C terminus of A{beta} forms the inside wall of the hollow core, which is supported by partial proteolysis analysis.
