| First Author | Kumar S | Year | 2011 |
| Journal | EMBO J | Volume | 30 |
| Issue | 11 | Pages | 2255-65 |
| PubMed ID | 21527912 | Mgi Jnum | J:173179 |
| Mgi Id | MGI:5013511 | Doi | 10.1038/emboj.2011.138 |
| Citation | Kumar S, et al. (2011) Extracellular phosphorylation of the amyloid beta-peptide promotes formation of toxic aggregates during the pathogenesis of Alzheimer's disease. EMBO J 30(11):2255-65 |
| abstractText | Alzheimer's disease (AD) is the most common form of dementia and associated with progressive deposition of amyloid beta-peptides (Abeta) in the brain. Abeta 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 Abeta domain promote the formation of neurotoxic Abeta assemblies and can cause early-onset AD. However, mechanisms that increase the aggregation of wild-type Abeta and cause the much more common sporadic forms of AD are largely unknown. Here, we show that extracellular Abeta 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 Abeta assemblies that represent nuclei for fibrillization. Phosphorylated Abeta was detected in the brains of transgenic mice and human AD brains and showed increased toxicity in Drosophila models as compared with non-phosphorylated Abeta. Phosphorylation of Abeta could represent an important molecular mechanism in the pathogenesis of the most common sporadic form of AD. |
