Extracellular phosphorylation of the amyloid β 2-peptide promotes formation of toxic aggregates during the pathogenesis of Alzheimer's disease

Alzheimer's disease (AD) is the most common form of dementia and associated with progressive deposition of amyloid β 2-peptides (Aβ 2) in the brain. Aβ 2 derives by sequential proteolytic processing of the amyloid precursor protein by β 2-and β 3-secretases. Rare mutations that lead to amino-acid substitutions within or close to the Aβ 2 domain promote the formation of neurotoxic Aβ 2 assemblies and can cause early-onset AD. However, mechanisms that increase the aggregation of wild-type Aβ 2 and cause the much more common sporadic forms of AD are largely unknown. Here, we show that extracellular Aβ 2 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 2 assemblies that represent nuclei for fibrillization. Phosphorylated Aβ 2 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 2. Phosphorylation of Aβ 2 could represent an important molecular mechanism in the pathogenesis of the most common sporadic form of AD. © 2011 European Molecular Biology Organization.