Phosphorylation of amyloid beta (Aβ) peptides - A trigger for formation of toxic aggregates in Alzheimer's disease

Alzheimer's disease (AD) is the most common form of dementia and associated with the progressive accumulation of amyloid beta-peptides (A beta) in form of extracellular amyloid plaques in the human brain. A critical role of A beta in the pathogenesis of AD is strongly supported by gene mutations that cause early-onset familial forms of the disease. Such mutations have been identified in the APP gene itself and in presenilin 1 and 2. Importantly, all the identified mutations commonly lead to early deposition of extracellular plaques likely by increasing the generation and/or aggregation of A beta. However, such mutations are very rare and molecular mechanisms that might trigger aggregation and deposition of A beta, in the most common late onset AD are largely unknown. We recently demonstrated that extracellular A beta undergoes phosphorylation by a cell surface-localized or secreted form of protein kinase A. The phosphorylation of serine residue 8 promotes aggregation by stabilization of beta-sheet conformation of A beta and increased formation of oligomeric A beta aggregates 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. Together, these findings demonstrate a novel molecular mechanism that triggers aggregation and toxicity of A beta. Thus, phosphorylation of A beta could be relevant in the pathogenesis of late onset AD. The identification of extracellular protein kinase A should also stimulate pharmacological approaches to decrease A beta phosphorylation in the therapy and/ or prevention of AD.