Brain Advance Access published online on January 20, 2009
Brain, doi:10.1093/brain/awn349
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Detection of elevated levels of soluble 
-synuclein oligomers in post-mortem brain extracts from patients with dementia with Lewy bodies
1 Division of Biomedical and Life Sciences, School of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK 2 Institute of Medical Biochemistry, University of Aarhus, Denmark 3 Clinical Neuroscience Research Group, School of Translational Medicine, University of Manchester Hope Hospital, Salford, M6 8HD, UK 4 Department of Biochemistry, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
Correspondence to:
Dr Omar M. El-Agnaf, Department of Biochemistry, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates E-mail: o.elagnaf{at}uaeu.ac.ae
A number of neurodegenerative diseases including Parkinson's disease, dementia with Lewy bodies (DLB) and multiple system atrophy are characterized by the formation and intraneuronal accumulation of fibrillar aggregates of 
-synuclein (-syn) protein in affected brain regions. These and other findings suggest that the accumulation of -syn in the brain plays an important role in the pathogenesis of these diseases. However, more recently it has been reported that early amyloid aggregates or ‘soluble oligomers’ are the pathogenic species that lead to neurodegeneration and neuronal cell death rather than the later ‘mature fibrils’. In this study, we investigated the presence of -syn oligomers in brain lysates prepared from frozen post-mortem brains of normal, Alzheimer's disease and DLB patients. The brain extracts were subjected to high speed centrifugation, to remove insoluble -syn aggregates, followed by specific detection of soluble oligomers in the supernatants by employing FILA-1, an antibody that specifically binds to -syn aggregates, but not to -syn monomers, or to tau or β-amyloid aggregates. Using this novel enzyme-linked immunosorbent assay (ELISA) method to quantify the amounts of -syn oligomers in the brain extracts, our data clearly show an increase in the levels of soluble oligomers of -syn in the DLB brains compared to those with Alzheimer's disease and the controls (P < 0.0001). Our findings provide strong evidence to support the contention that elevated soluble oligomers of -syn are involved in the pathogenesis of DLB. Furthermore, these findings establish FILA-1 as a very sensitive tool for the detection of oligomeric forms of -syn in human brain lysates.
Key Words:
dementia with Lewy bodies; neurodegeneration; amyloid oligomers; -synuclein
Abbreviations:
Aβ, β-amyloid protein; -syn, -synuclein; DAB, diaminobenzidine; DLB, dementia with Lewy bodies; ELISA, enzyme-linked immunosorbent assay; LBs, Lewy bodies; NFTs, neurofibrillary tangles; PBS, phosphate buffered saline; SDS, sodium dodecyl sulphate; SPs, senile plaques
Received August 8, 2008. Revised November 18, 2008. Accepted November 19, 2008.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. Tong, H. Wong, M. Guttman, L. C. Ang, L. S. Forno, M. Shimadzu, A. H. Rajput, M. D. Muenter, S. J. Kish, O. Hornykiewicz, et al. Brain {alpha}-synuclein accumulation in multiple system atrophy, Parkinson's disease and progressive supranuclear palsy: a comparative investigation Brain, November 10, 2009; (2009) awp282v1. [Abstract] [Full Text] [PDF]
|
|