Alzheimer's disease is a neurodegenerative disorder characterized by the accumulation of amyloid plaques in the brain. This amyloid primarily contains amyloid-β (Aβ), a 39- to 43-aa peptide derived from the proteolytic cleavage of the endogenous amyloid precursor protein. The 42-residue-length Aβ peptide (Aβ 1-42), the most abundant Aβ 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 Aβ 1-42 peptides self-aggregate into stable but poorly-ordered helical filaments. We determined their structure to ≈10-Å 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 Aβ 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 oppositeprotofilament. This model of mature Aβ 1-42 fibrils is markedly different from previous cryoEM models of Aβ 1-40 fibrils. In our model, the C terminus of Aβ forms the inside wall of the hollow core, which is supported by partial proteolysis analysis.
|Number of pages||6|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Mar 24 2009|