APP Cleavage and Amyloid-beta Degradation

Under normal conditions, the majority of amyloid precursor protein (APP) cleavage is believed to be alpha-secretase dependent and occur within the amyloid-beta peptide (A-beta) sequence. However, changes that occur during aging and neurodegenerative diseases, such as Alzheimers, drive an increased proportion of amyloidogenic processing through BACE-1 and gamma-secretase.

Subsequent accumulation of A-beta in the brain is dependent on the rates of generation and degradation. A-beta peptides within the cell are subjected to degradation by endothelin-converting enzyme (ECE), insulin-degrading enzyme (IDE) and Cystatin-C. Breakdown of extracellular A-beta peptides is achieved through neprilysin, angiotensin converting enzyme (ACE), matrix metalloproteases (MMP) and via plasmin.