Detection of elevated levels of soluble α-synuclein oligomers in post-mortem brain extracts from patients with dementia with Lewy bodies

Katerina E. Paleologou, Christine L. Kragh, David M.A. Mann, Sultan A. Salem, Rania Al-Shami, David Allsop, Ahmed H. Hassan, Poul H. Jensen, Omar M.A. El-Agnaf

Research output: Contribution to journalArticle

149 Citations (Scopus)

Abstract

A number of neurodegenerative diseases including Parkinsons disease, dementia with Lewy bodies (DLB) and multiple system atrophy are characterized by the formation and intraneuronal accumulation of fibrillar aggregates of α-synuclein (α-syn) protein in affected brain regions. These and other findings suggest that the accumulation of α-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 α-syn oligomers in brain lysates prepared from frozen post-mortem brains of normal, Alzheimers disease and DLB patients. The brain extracts were subjected to high speed centrifugation, to remove insoluble α-syn aggregates, followed by specific detection of soluble oligomers in the supernatants by employing FILA-1, an antibody that specifically binds to α-syn aggregates, but not to α-syn monomers, or to tau or β-amyloid aggregates. Using this novel enzyme-linked immunosorbent assay (ELISA) method to quantify the amounts of α-syn oligomers in the brain extracts, our data clearly show an increase in the levels of soluble oligomers of α-syn in the DLB brains compared to those with Alzheimers disease and the controls (P < 0.0001). Our findings provide strong evidence to support the contention that elevated soluble oligomers of α-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 α-syn in human brain lysates.

Original languageEnglish
Pages (from-to)1093-1101
Number of pages9
JournalBrain
Volume132
Issue number4
DOIs
Publication statusPublished - Apr 2009

    Fingerprint

Keywords

  • Amyloid oligomers
  • Dementia with Lewy bodies
  • Neurodegeneration
  • α-synuclein

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Paleologou, K. E., Kragh, C. L., Mann, D. M. A., Salem, S. A., Al-Shami, R., Allsop, D., Hassan, A. H., Jensen, P. H., & El-Agnaf, O. M. A. (2009). Detection of elevated levels of soluble α-synuclein oligomers in post-mortem brain extracts from patients with dementia with Lewy bodies. Brain, 132(4), 1093-1101. https://doi.org/10.1093/brain/awn349