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