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Although APP mutations associated with inherited forms of Alzheimer’s disease (AD) are relatively rare, detailed studies of these mutations may prove critical for gaining important insights into the mechanism(s) and etiology of AD. Here, we present a detailed biophysical characterization of the stru...
| Main Authors: | , , , , , , |
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| Other Authors: | |
| Format: | Text |
| Language: | English |
| Subjects: | |
| Online Access: | http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.389.4595 http://walz.med.harvard.edu/Publications/PDFs/Lashuel-JMB-2003.pdf |
| Summary: | Although APP mutations associated with inherited forms of Alzheimer’s disease (AD) are relatively rare, detailed studies of these mutations may prove critical for gaining important insights into the mechanism(s) and etiology of AD. Here, we present a detailed biophysical characterization of the structural properties of protofibrils formed by the Arctic variant (E22G) of amyloid-b protein (Ab40 ARC) as well as the effect of Ab40 WT on the distribution of the protofibrillar species formed by Ab40 ARC by characterizing biologically relevant mixtures of both proteins that may mimic the situation in the heterozygous patients. These studies revealed that the Arctic mutation accelerates both Ab oligomerization and fibrillogenesis in vitro. In addition, Ab40 ARC was observed to affect both the morphology and the size distribution of Ab protofibrils. Electron microscopy examination of the protofibrils formed by Ab40ARC revealed several morphologies, including: (1) relatively compact spherical particles roughly 4–5 nm in diameter; (2) annular pore-like protofibrils; (3) large spherical |
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