Nitration of Tyrosine 10 Critically Enhances Amyloid β Aggregation and Plaque Formation

Part of the inflammatory response in Alzheimer's disease (AD) is the upregulation of the inducible nitric oxide synthase (NOS2) resulting in increased NO production. NO contributes to cell signaling by inducing posttranslational protein modifications. Under pathological conditions there is a shift from the signal transducing actions to the formation of protein tyrosine nitration by secondary products like peroxynitrite and nitrogen dioxide. We identified amyloid beta (A beta) as an NO target, which is nitrated at tyrosine 10 (3NTyr(10)-A beta). Nitration of A beta accelerated its aggregation and was detected in the core of A beta plaques of APP/PS1 mice and AD brains. NOS2 deficiency or oral treatment with the NOS2 inhibitor L-NIL strongly decreased 3NTyr(10)-A beta, overall A beta deposition and cognitive dysfunction in APP/PS1 mice. Further, injection of 3NTyr(10)-A beta into the brain of young APP/PS1 mice induced beta-amyloidosis. This suggests a disease modifying role for NOS2 in AD and therefore represents a potential therapeutic target.