Jessica M Mc Donald1, Tiernan T O'Malley2, Wen Liu1, Alexandra J Mably1, Gunnar Brinkmalm3, Erik Portelius3, William M Wittbold4, Matthew P Frosch5, Dominic M Walsh6. 1. Laboratory for Neurodegenerative Research, Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Harvard Institutes of Medicine, Boston, MA, USA. 2. Laboratory for Neurodegenerative Research, Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Harvard Institutes of Medicine, Boston, MA, USA; School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Republic of Ireland. 3. Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, University of Göteborg, Sahlgrenska University Hospital, Mölndal, Sweden. 4. Wyatt Technology Corporation, Woburn, MA, USA. 5. Massachusetts General Hospital and Harvard Medical School, Massachusetts General Institute for Neurodegenerative Disease, Charlestown, MA, USA. 6. Laboratory for Neurodegenerative Research, Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Harvard Institutes of Medicine, Boston, MA, USA. Electronic address: dwalsh3@partners.org.
Abstract
INTRODUCTION: Much knowledge about amyloid β (Aβ) aggregation and toxicity has been acquired using synthetic peptides and mouse models, whereas less is known about soluble Aβ in human brain. METHODS: We analyzed aqueous extracts from multiple AD brains using an array of techniques. RESULTS: Brains can contain at least four different Aβ assembly forms including: (i) monomers, (ii) a ∼7 kDa Aβ species, and larger species (iii) from ∼30-150 kDa, and (iv) >160 kDa. High molecular weight species are by far the most prevalent and appear to be built from ∼7 kDa Aβ species. The ∼7 kDa Aβ species resist denaturation by chaotropic agents and have a higher Aβ42/Aβ40 ratio than monomers, and are unreactive with antibodies to Asp1 of Ab or APP residues N-terminal of Asp1. DISCUSSION: Further analysis of brain-derived ∼7 kDa Aβ species, the mechanism by which they assemble and the structures they form should reveal therapeutic and diagnostic opportunities.
INTRODUCTION: Much knowledge about amyloid β (Aβ) aggregation andtoxicity has been acquired using synthetic peptides andmouse models, whereas less is known about soluble Aβ in human brain. METHODS: We analyzed aqueous extracts from multiple AD brains using an array of techniques. RESULTS: Brains can contain at least four different Aβ assembly forms including: (i) monomers, (ii) a ∼7 kDa Aβ species, and larger species (iii) from ∼30-150 kDa, and (iv) >160 kDa. High molecular weight species are by far the most prevalent and appear to be built from ∼7 kDa Aβ species. The ∼7 kDa Aβ species resist denaturation by chaotropic agents and have a higher Aβ42/Aβ40 ratio than monomers, and are unreactive with antibodies to Asp1 of Ab or APP residues N-terminal of Asp1. DISCUSSION: Further analysis of brain-derived ∼7 kDa Aβ species, the mechanism by which they assemble and the structures they form should reveal therapeutic and diagnostic opportunities.
Authors: C A McLean; R A Cherny; F W Fraser; S J Fuller; M J Smith; K Beyreuther; A I Bush; C L Masters Journal: Ann Neurol Date: 1999-12 Impact factor: 10.422
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