Extracellular phosphorylation of the amyloid ?-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 ?-peptides (A?) in the brain. A? derives by sequential proteolytic processing of the amyloid precursor protein by ?- and ?-secretases. Rare mutations that lead to amino-acid substitutions within or close to the A? domain promote the formation of neurotoxic A? assemblies and can cause early-onset AD. However, mechanisms that increase the aggregation of wild-type A? and cause the much more common sporadic forms of AD are largely unknown. Here, we show that extracellular A? 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? assemblies that represent nuclei for fibrillization. Phosphorylated A? 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?. Phosphorylation of A? could represent an important molecular mechanism in the pathogenesis of the most common sporadic form of AD.

SUBMITTER: Kumar S 

PROVIDER: S-EPMC3117653 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature