Phosphorylation of a full length amyloid-β peptide modulates its amyloid aggregation, cell binding and neurotoxic properties

Amyloid beta peptide (A beta) is the major protein component of the amyloid plaques that are present in the brains of Alzheimer's disease (AD) patients. A beta 42 peptide is a known neurotoxic agent that binds to neurons and, under specific aggregation conditions, triggers cell death. A beta peptide can undergo specific amino acid posttranslational modifications, such as phosphorylation, that are important for modulating its proteolytic degradation, aggregation, binding to lipid membranes and neurotoxic functions. Peptides phosphorylated at serine 8 in full-length 42 (pA beta 42) were synthesised and compared to native A beta 42 peptide. Their secondary structures, aggregation properties and interactions with plasma membranes of primary cortical neurons were investigated. The results revealed that pA beta 42 has increased beta-sheet formation with rapid amyloid formation in a synthetic lipid environment, which was associated with increased cellular binding but concomitant diminished neurotoxicity. Our data support the notion that phosphorylation of A beta 42 promotes the formation of amyloid plaques in the brain, which lack the neurotoxic properties associated with oligomeric species causing pathogenesis in AD.