title: The Aggregation Paths and Products of Aβ42 Dimers Are Distinct from Those of the Aβ42 Monomer.
abstract: Extracts of Alzheimer's disease (AD) brain that contain what appear to be sodium dodecyl sulfate-stable amyloid β-protein (Aβ) dimers potently block LTP and impair memory consolidation. Brain-derived dimers can be physically separated the Aβ monomer, consist primarily of Aβ42, and resist denaturation by chaotropic agents. In nature, covalently cross-linked Aβ dimers could be generated in two ways: by the formation of a dityrosine (DiY) or an isopeptide ε-(γ-glutamyl)-lysine (Q-K) bond. We enzymatically cross-linked recombinant Aβ42 monomer to produce DiY and Q-K dimers and then used a range of biophysical methods to study their aggregation. Both Q-K and DiY dimers aggregate to form soluble assemblies distinct from the fibrillar aggregates formed by the Aβ monomer. The results suggest that the cross-links disfavor fibril formation from Aβ dimers, thereby enhancing the concentration of soluble aggregates akin to those in aqueous extracts of AD brain. Thus, it seems that Aβ dimers may play an important role in determining the formation of soluble rather than insoluble aggregates.
authors.affiliation: Laboratory for Neurodegenerative Research, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School , Boston, Massachusetts 02115, United States.|School of Biomolecular and Biomedical Science, University College Dublin , Dublin 4, Republic of Ireland.
authors.forename: Tiernan T
authors.initials: TT
authors.lastname: O'Malley
authors.affiliation: Wyatt Technology Corporation , 18 Commerce Way, Woburn, Massachusetts 01801, United States.
authors.forename: William M
authors.initials: WM
authors.lastname: Witbold
authors.affiliation: Department of Biochemistry and Structural Biology, Lund University , PO Box 124, SE221 00 Lund, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Linse
authors.affiliation: Laboratory for Neurodegenerative Research, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Dominic M
authors.initials: DM
authors.lastname: Walsh
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D019281:Dimerization; D005453:Fluorescence; D013058:Mass Spectrometry; D008970:Molecular Weight
chemical_list: D016229:Amyloid beta-Peptides