The aqueous phase of Alzheimer's disease brain contains assemblies built from ∼4 and ∼7 kDa Aβ species

Jessica M Mc Donald; Tiernan T O'Malley; Wen Liu; Alexandra J Mably; Gunnar Brinkmalm; Erik Portelius; William M Wittbold 3rd; Matthew P Frosch; Dominic M Walsh

doi:10.1016/j.jalz.2015.01.005

The aqueous phase of Alzheimer's disease brain contains assemblies built from ∼4 and ∼7 kDa Aβ species

Alzheimers Dement. 2015 Nov;11(11):1286-305. doi: 10.1016/j.jalz.2015.01.005. Epub 2015 Apr 4.

Authors

Jessica M Mc Donald¹, Tiernan T O'Malley², Wen Liu¹, Alexandra J Mably¹, Gunnar Brinkmalm³, Erik Portelius³, William M Wittbold 3rd⁴, Matthew P Frosch⁵, Dominic M Walsh⁶

Affiliations

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: [email protected].

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.

Keywords: Alzheimer's disease; Amyloid β-protein; Oligomers; SDS-Stable dimer.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Alzheimer Disease / metabolism*
Amyloid beta-Peptides / metabolism*
Blotting, Western
Electrophoresis, Polyacrylamide Gel
Enzyme-Linked Immunosorbent Assay
Female
Frontal Lobe / metabolism*
Humans
Immunoprecipitation
Male
Mass Spectrometry
Middle Aged
Molecular Weight
Protein Multimerization
Temporal Lobe / metabolism*
Water / metabolism*

Substances

Amyloid beta-Peptides
Water

Abstract

Publication types

MeSH terms

Substances

Grants and funding