title: Extracellular phosphorylation of the amyloid β-peptide promotes formation of toxic aggregates during the pathogenesis of Alzheimer's disease.
abstract: Alzheimer's disease (AD) is the most common form of dementia and associated with progressive deposition of amyloid β-peptides (Aβ) in the brain. Aβ derives by sequential proteolytic processing of the amyloid precursor protein by β- and γ-secretases. Rare mutations that lead to amino-acid substitutions within or close to the Aβ domain promote the formation of neurotoxic Aβ assemblies and can cause early-onset AD. However, mechanisms that increase the aggregation of wild-type Aβ and cause the much more common sporadic forms of AD are largely unknown. Here, we show that extracellular Aβ undergoes phosphorylation by protein kinases at the cell surface and in cerebrospinal fluid of the human brain. Phosphorylation of serine residue 8 promotes formation of oligomeric Aβ assemblies that represent nuclei for fibrillization. Phosphorylated Aβ was detected in the brains of transgenic mice and human AD brains and showed increased toxicity in Drosophila models as compared with non-phosphorylated Aβ. Phosphorylation of Aβ could represent an important molecular mechanism in the pathogenesis of the most common sporadic form of AD.
authors.affiliation: Department of Neurology, University of Bonn, Bonn, Germany.
authors.forename: Sathish
authors.initials: S
authors.lastname: Kumar
authors.forename: Nasrollah
authors.initials: N
authors.lastname: Rezaei-Ghaleh
authors.forename: Dick
authors.initials: D
authors.lastname: Terwel
authors.forename: Dietmar R
authors.initials: DR
authors.lastname: Thal
authors.forename: Mélisande
authors.initials: M
authors.lastname: Richard
authors.forename: Michael
authors.initials: M
authors.lastname: Hoch
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Mc Donald
authors.forename: Ullrich
authors.initials: U
authors.lastname: Wüllner
authors.forename: Konstantin
authors.initials: K
authors.lastname: Glebov
authors.forename: Michael T
authors.initials: MT
authors.lastname: Heneka
authors.forename: Dominic M
authors.initials: DM
authors.lastname: Walsh
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
authors.forename: Jochen
authors.initials: J
authors.lastname: Walter
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000473:pathology; D004195:Disease Models, Animal; D004330:Drosophila; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D010766:Phosphorylation; D011489:Protein Denaturation
chemical_list: D016229:Amyloid beta-Peptides