Journal
EMBO JOURNAL
Volume 30, Issue 11, Pages 2255-2265Publisher
WILEY
DOI: 10.1038/emboj.2011.138
Keywords
Alzheimer's disease; amyloid beta; oligomers; post-translational modification; protein folding
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Funding
- Deutsche Forschungsgemeinschaft (DFG) [WA1477/6, SFB645, KFo177]
- Max Planck Society
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Alzheimer's disease (AD) is the most common form of dementia and associated with progressive deposition of amyloid beta-peptides (A beta) in the brain. A beta derives by sequential proteolytic processing of the amyloid precursor protein by beta- and gamma-secretases. Rare mutations that lead to amino-acid substitutions within or close to the A beta domain promote the formation of neurotoxic A beta assemblies and can cause early-onset AD. However, mechanisms that increase the aggregation of wild-type A beta and cause the much more common sporadic forms of AD are largely unknown. Here, we show that extracellular A beta 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 A beta assemblies that represent nuclei for fibrillization. Phosphorylated A beta was detected in the brains of transgenic mice and human AD brains and showed increased toxicity in Drosophila models as compared with non-phosphorylated A beta. Phosphorylation of A beta could represent an important molecular mechanism in the pathogenesis of the most common sporadic form of AD. The EMBO Journal (2011) 30, 2255-2265. doi:10.1038/emboj.2011.138; Published online 28 April 2011
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