High molecular mass assemblies of amyloid-beta oligomers bind prion protein in patients with Alzheimer's disease
2014 | journal article. A publication with affiliation to the University of Göttingen.
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High molecular mass assemblies of amyloid-beta oligomers bind prion protein in patients with Alzheimer's disease
Dohler, F.; Sepulveda-Falla, D.; Krasemann, S.; Altmeppen, H.; Schlueter, H.; Hildebrand, D. & Zerr, I. et al. (2014)
Brain, 137 pp. 873-886. DOI: https://doi.org/10.1093/brain/awt375
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- Authors
- Dohler, Frank; Sepulveda-Falla, Diego; Krasemann, Susanne; Altmeppen, Hermann; Schlueter, Hartmut; Hildebrand, Diana; Zerr, Inga; Matschke, Jakob; Glatzel, Markus
- Abstract
- Alzheimer's disease is the most common form of dementia and the generation of oligomeric species of amyloid-beta is causal to the initiation and progression of it. Amyloid-beta oligomers bind to the N-terminus of plasma membrane-beta ound cellular prion protein (PrPC) initiating a series of events leading to synaptic degeneration. Composition of bound amyloid-beta oligomers, binding regions within PrPC, binding affinities and modifiers of this interaction have been almost exclusively studied in cell culture or murine models of Alzheimer's disease and our knowledge on PrPC-amyloid-beta interaction in patients with Alzheimer's disease is limited regarding occurrence, binding regions in PrPC, and size of bound amyloid-beta oligomers. Here we employed a PrPC amyloid-beta binding assay and size exclusion chromatography on neuropathologically characterized Alzheimer's disease and non-demented control brains (n = 15, seven female, eight male, average age: 79.2 years for Alzheimer's disease and n = 10, three female, seven male, average age: 66.4 years for controls) to investigate amyloid-beta-PrPC interaction. PrPC-amyloid-beta binding always occurred in Alzheimer's disease brains and was never detected in non-demented controls. Neither expression level of PrPC nor known genetic modifiers of Alzheimer's disease, such as the PrPC codon 129 polymorphism, influenced this interaction. In Alzheimer's disease brains, binding of amyloid-beta to PrPC occurred via the PrPC N-terminus. For synthetic amyloid-beta(42), small oligomeric species showed prominent binding to PrPC, whereas in Alzheimer's disease brains larger protein assemblies containing amyloid-beta(42) bound efficiently to PrPC. These data confirm Alzheimer's disease specificity of binding of amyloid-beta to PrPC via its N-terminus in a large cohort of Alzheimer's disease/control brains. Differences in sizes of separated protein fractions between synthetic and brain-derived amyloid-beta binding to PrPC suggest that larger assemblies of amyloid-beta or additional non-amyloid-beta components may play a role in binding of amyloid-beta(42) to PrPC in Alzheimer's disease.
- Issue Date
- 2014
- Status
- published
- Publisher
- Oxford Univ Press
- Journal
- Brain
- ISSN
- 1460-2156; 0006-8950