Accelerating Amyloid- Fibrillization Reduces Oligomer Levels and Functional Deficits in Alzheimer Disease Mouse Models*□S
Many proteins suspected of causing neurodegenerative dis-eases exist in diverse assembly states. For most, it is unclear whether shifts from one state to another would be helpful or harmful. We used mutagenesis to change the assembly state of Alzheimer disease (AD)-associated amyloid- (A) peptides....
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| Format: | Text |
| Language: | English |
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| Online Access: | http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.577.2067 http://www2.neuroscience.umn.edu/eanwebsite/PDF GJClub/J Biol Chem 282 23818 2007.pdf |
| Summary: | Many proteins suspected of causing neurodegenerative dis-eases exist in diverse assembly states. For most, it is unclear whether shifts from one state to another would be helpful or harmful. We used mutagenesis to change the assembly state of Alzheimer disease (AD)-associated amyloid- (A) peptides. In vitro, the “Arctic”mutation (AE22G) acceleratedA fibrilliza-tion but decreased the abundance of nonfibrillar A assemblies, compared with wild-type A. In human amyloid precursor pro-tein (hAPP) transgenic mice carrying mutations adjacent to A that increase A production, addition of the Arctic mutation markedly enhanced the formation of neuritic amyloid plaques but reduced the relative abundance of a specific nonfibrillar A assembly (A*56). Mice overexpressing Arctic mutant or wild-type A had similar behavioral and neuronal deficits when they were matched for A*56 levels but had vastly different plaque |
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