Dutch, Flemish, Italian, and Arctic mutations of APP and resistance of Aβ to physiologically relevant proteolytic degradation

The Dutch, Flemish, Italian, and Arctic mutations in the amyloid precursor protein (APP) gene encode changes within the sequence of the amyloid β peptide (Aβ) and cause presenile cerebral amyloid angiopathy, cerebral parenchymal amyloidosis, or both. These disorders are caused by accumulation of Aβ, with no evidence of increased Aβ production. Our results showed that these mutations in Aβ make it resistant to proteolytic degradation by neprilysin, the peptidase with the most important role in catabolism of Aβ in the brain. These mutations in Aβ could thus be pathogenic not only by facilitating fibrillogenesis but also by extending the half-life of Aβ in the brain.