Elucidating molecular mass and shape of a neurotoxic aβ oligomer

Adriano Sebollela*, Gina Mirela Mustata, Kevin Luo, Pauline T. Velasco, Kirsten L. Viola, Erika N. Cline, Gajendra S. Shekhawat, Kyle C. Wilcox, Vinayak P. Dravid, William L. Klein

*Corresponding author for this work

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Alzheimer's disease (AD), the most prevalent type of dementia, has been associated with the accumulation of amyloid β oligomers (AβOs) in the central nervous system. AβOs vary widely in size, ranging from dimers to larger than 100 kDa. Evidence indicates that not all oligomers are toxic, and there is yet no consensus on the size of the actual toxic oligomer. Here we used NU4, a conformation-dependent anti-AβO monoclonal antibody, to investigate size and shape of a toxic AβO assembly. By using size-exclusion chromatography and immuno-based detection, we isolated an AβO-NU4 complex amenable for biochemical and morphological studies. The apparent molecular mass of the NU4-targeted oligomer was 80 kDa. Atomic force microscopy imaging of the AβO-NU4 complex showed a size distribution centered at 5.37 nm, an increment of 1.5 nm compared to the size of AβOs (3.85 nm). This increment was compatible with the size of NU4 (1.3 nm), suggesting a 1:1 oligomer to NU4 ratio. NU4-reactive oligomers extracted from AD human brain concentrated in a molecular mass range similar to that found for in vitro prepared oligomers, supporting the relevance of the species herein studied. These results represent an important step toward understanding the connection between AβO size and toxicity. (Figure Presented).

Original languageEnglish (US)
Pages (from-to)1238-1245
Number of pages8
JournalACS Chemical Neuroscience
Volume5
Issue number12
DOIs
StatePublished - Dec 17 2014

Keywords

  • AFM
  • Alzheimer's disease
  • Aβ oligomer
  • NU4 antibody
  • Neurotoxicity

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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  • Cite this

    Sebollela, A., Mustata, G. M., Luo, K., Velasco, P. T., Viola, K. L., Cline, E. N., Shekhawat, G. S., Wilcox, K. C., Dravid, V. P., & Klein, W. L. (2014). Elucidating molecular mass and shape of a neurotoxic aβ oligomer. ACS Chemical Neuroscience, 5(12), 1238-1245. https://doi.org/10.1021/cn500156r