OUP user menu

High molecular mass assemblies of amyloid-β oligomers bind prion protein in patients with Alzheimer’s disease

Frank Dohler, Diego Sepulveda-Falla, Susanne Krasemann, Hermann Altmeppen, Hartmut Schlüter, Diana Hildebrand, Inga Zerr, Jakob Matschke, Markus Glatzel
DOI: http://dx.doi.org/10.1093/brain/awt375 873-886 First published online: 10 February 2014


Alzheimer’s disease is the most common form of dementia and the generation of oligomeric species of amyloid-β is causal to the initiation and progression of it. Amyloid-β oligomers bind to the N-terminus of plasma membrane-bound cellular prion protein (PrPC) initiating a series of events leading to synaptic degeneration. Composition of bound amyloid-β 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-β interaction in patients with Alzheimer’s disease is limited regarding occurrence, binding regions in PrPC, and size of bound amyloid-β oligomers. Here we employed a PrPC-amyloid-β 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-β-PrPC interaction. PrPC-amyloid-β 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-β to PrPC occurred via the PrPC N-terminus. For synthetic amyloid-β42, small oligomeric species showed prominent binding to PrPC, whereas in Alzheimer’s disease brains larger protein assemblies containing amyloid-β42 bound efficiently to PrPC. These data confirm Alzheimer’s disease specificity of binding of amyloid-β 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-β binding to PrPC suggest that larger assemblies of amyloid-β or additional non-amyloid-β components may play a role in binding of amyloid-β42 to PrPC in Alzheimer’s disease.

  • prion protein
  • PrPC
  • Alzheimer’s disease
  • amyloid-β oligomers
  • amyloid-β neurodegeneration
  • Abbreviations
    amyloid-β PrP interaction assay
    prion protein
  • View Full Text