Amyloid-beta oligomerization in Alzheimer dementia versus high-pathology controls
Article first published online: 7 DEC 2012
Copyright © 2012 American Neurological Association
Annals of Neurology
Volume 73, Issue 1, pages 104–119, January 2013
How to Cite
Esparza, T. J., Zhao, H., Cirrito, J. R., Cairns, N. J., Bateman, R. J., Holtzman, D. M. and Brody, D. L. (2013), Amyloid-beta oligomerization in Alzheimer dementia versus high-pathology controls. Ann Neurol., 73: 104–119. doi: 10.1002/ana.23748
- Issue published online: 1 FEB 2013
- Article first published online: 7 DEC 2012
- Accepted manuscript online: 1 SEP 2012 03:46AM EST
- Manuscript Accepted: 27 AUG 2012
- Manuscript Revised: 8 AUG 2012
- Manuscript Received: 20 OCT 2011
Although amyloid-beta (Aβ) peptide deposition into insoluble plaques is a pathological hallmark of Alzheimer disease; soluble oligomeric Aβ has been hypothesized to more directly underlie impaired learning and memory in dementia of the Alzheimer type. However, the lack of a sensitive, specific, and quantitative assay for Aβ oligomers has hampered rigorous tests of this hypothesis.
We developed a plate-based single molecule counting fluorescence immunoassay for oligomeric Aβ sensitive to low pg/ml concentrations of synthetic Aβ dimers using the same Aβ-specific monoclonal antibody to both capture and detect Aβ. The Aβ oligomer assay does not recognize monomeric Aβ, amyloid precursor protein, or other non-Aβ peptide oligomers.
Aβ oligomers were detected in aqueous cortical lysates from patients with dementia of the Alzheimer type and nondemented patients with Aβ plaque pathology. However, Aβ oligomer concentrations in demented patients' lysates were tightly correlated with Aβ plaque coverage (r = 0.88), but this relationship was weaker in those from nondemented patients (r = 0.30) despite equivalent Aβ plaque pathology. The ratio of Aβ oligomer levels to plaque density fully distinguished demented from nondemented patients, with no overlap between groups in this derived variable. Other Aβ and plaque measures did not distinguish demented from nondemented patients. Aβ oligomers were not detected in cerebrospinal fluid with this assay.
The results raise the intriguing hypothesis that the linkage between plaques and oligomers may be a key pathophysiological event underlying dementia of the Alzheimer type. This Aβ oligomer assay may be useful for many tests of the oligomer hypothesis. ANN NEUROL 2013