title: High molecular mass assemblies of amyloid-β oligomers bind prion protein in patients with Alzheimer's disease.
abstract: 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 (PrP(C)) initiating a series of events leading to synaptic degeneration. Composition of bound amyloid-β oligomers, binding regions within PrP(C), 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 PrP(C)-amyloid-β interaction in patients with Alzheimer's disease is limited regarding occurrence, binding regions in PrP(C), and size of bound amyloid-β oligomers. Here we employed a PrP(C)-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-PrP(C) interaction. PrP(C)-amyloid-β binding always occurred in Alzheimer's disease brains and was never detected in non-demented controls. Neither expression level of PrP(C) nor known genetic modifiers of Alzheimer's disease, such as the PrP(C) codon 129 polymorphism, influenced this interaction. In Alzheimer's disease brains, binding of amyloid-β to PrP(C) occurred via the PrP(C) N-terminus. For synthetic amyloid-β42, small oligomeric species showed prominent binding to PrP(C), whereas in Alzheimer's disease brains larger protein assemblies containing amyloid-β42 bound efficiently to PrP(C). These data confirm Alzheimer's disease specificity of binding of amyloid-β to PrP(C) 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 PrP(C) suggest that larger assemblies of amyloid-β or additional non-amyloid-β components may play a role in binding of amyloid-β42 to PrP(C) in Alzheimer's disease.
authors: 1 Institute of Neuropathology, University Medical Centre Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors: Frank
authors: F
authors: Dohler
authors: Diego
authors: D
authors: Sepulveda-Falla
authors: Susanne
authors: S
authors: Krasemann
authors: Hermann
authors: H
authors: Altmeppen
authors: Hartmut
authors: H
authors: Schlüter
authors: Diana
authors: D
authors: Hildebrand
authors: Inga
authors: I
authors: Zerr
authors: Jakob
authors: J
authors: Matschke
authors: Markus
authors: M
authors: Glatzel
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D002850:Chromatography, Gel; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics; D018621:PrPC Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding
chemical_list: D016229:Amyloid beta-Peptides; C512656:PRNP protein, human; D018621:PrPC Proteins; D000072002:Prion Proteins; D011328:Prions
keywords: Alzheimer’s disease; PrPC; amyloid-β neurodegeneration; amyloid-β oligomers; prion protein