Modification of γ-secretase by nitrosative stress links neuronal ageing to sporadic Alzheimer's disease

Inherited familial Alzheimer's disease (AD) is characterized by small increases in the ratio of A beta 42 versus A beta 40 peptide which is thought to drive the amyloid plaque formation in the brain of these patients. Little is known however whether ageing, the major risk factor for sporadic AD, affects amyloid beta-peptide (A beta) generation as well. Here we demonstrate that the secretion of A beta is enhanced in an in vitro model of neuronal ageing, correlating with an increase in gamma-secretase complex formation. Moreover we found that peroxynitrite (ONOO-), produced by the reaction of superoxide anion with nitric oxide, promoted the nitrotyrosination of presenilin 1 (PS1), the catalytic subunit of gamma-secretase. This was associated with an increased association of the two PS1 fragments, PS1-CTF and PS1-NTF, which constitute the active catalytic centre. Furthermore, we found that peroxynitrite shifted the production of A beta towards A beta 42 and increased the A beta 42/A beta 40 ratio. Our work identifies nitrosative stress as a potential mechanistic link between ageing and AD.