The Library
Structural basis for increased toxicity of pathological Aβ42 : Aβ40Ratios in Alzheimer disease
Tools
Tools
Tools
Pauwels, Kris, Williams, Thomas L., Morris, Kyle L., Jonckheere, Wim, Vandersteen, Annelies, Kelly, Geoff, Schymkowitz, Joost, Rousseau, Frederic, Pastore, Annalisa, Serpell, Louise C. and Broersen, Kerensa (2012) Structural basis for increased toxicity of pathological Aβ42 : Aβ40Ratios in Alzheimer disease. Journal of Biological Chemistry, 287 (8). pp. 5650-5660. doi:10.1074/jbc.M111.264473 ISSN 0021-9258.
Research output not available from this repository.
Request-a-Copy directly from author or use local Library Get it For Me service.
Official URL: http://dx.doi.org/10.1074/jbc.M111.264473
Abstract
The ß-amyloid peptide (Aß) is directly related to neurotoxicity in Alzheimer disease (AD). The two most abundant alloforms of the peptide co-exist under normal physiological conditions in the brain in an Aß(42):Aß(40) ratio of â�¼1:9. This ratio is often shifted to a higher percentage of Aß(42) in brains of patients with familial AD and this has recently been shown to lead to increased synaptotoxicity. The molecular basis for this phenomenon is unclear. Although the aggregation characteristics of Aß(40) and Aß(42) individually are well established, little is known about the properties of mixtures. We have explored the biophysical and structural properties of physiologically relevant Aß(42):Aß(40) ratios by several techniques. We show that Aß(40) and Aß(42) directly interact as well as modify the behavior of the other. The structures of monomeric and fibrillar assemblies formed from Aß(40) and Aß(42) mixtures do not differ from those formed from either of these peptides alone. Instead, the co-assembly of Aß(40) and Aß(42) influences the aggregation kinetics by altering the pattern of oligomer formation as evidenced by a unique combination of solution nuclear magnetic resonance spectroscopy, high molecular weight mass spectrometry, and cross-seeding experiments. We relate these observations to the observed enhanced toxicity of relevant ratios of Aß(42):Aß(40) in synaptotoxicity assays and in AD patients.
| Item Type: | Journal Article | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Subjects: | R Medicine > RC Internal medicine | ||||||||||||
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||||||||||
| Library of Congress Subject Headings (LCSH): | Alzheimer's disease., Alzheimer's disease -- Molecular aspects., Molecular diagnosis., Amyloid beta-protein., Amyloid beta-protein -- Physiology. | ||||||||||||
| Journal or Publication Title: | Journal of Biological Chemistry | ||||||||||||
| Publisher: | American Society for Biochemistry and Molecular Biology | ||||||||||||
| ISSN: | 0021-9258 | ||||||||||||
| Official Date: | 17 February 2012 | ||||||||||||
| Dates: |
|
||||||||||||
| Volume: | 287 | ||||||||||||
| Number: | 8 | ||||||||||||
| Page Range: | pp. 5650-5660 | ||||||||||||
| DOI: | 10.1074/jbc.M111.264473 | ||||||||||||
| Status: | Peer Reviewed | ||||||||||||
| Publication Status: | Published | ||||||||||||
| Access rights to Published version: | Restricted or Subscription Access | ||||||||||||
| RIOXX Funder/Project Grant: |
|
Request changes or add full text files to a record
Repository staff actions (login required)
 |
View Item |
