Amyloid-beta precursor protein processing enzymes (APP processing enzymes)

The Amyloid-beta precursor protein (APP) processing enzymes, specifically Beta-secretase 1 (BACE1) and the multi-subunit Gamma-secretase complex, are the primary drivers of the amyloidogenic pathway (UniProt P56817, P49768). BACE1 initiates the process by cleaving APP at the beta-site, followed by Gamma-secretase-mediated intramembrane proteolysis, which releases Amyloid-beta (Aβ) peptides of varying lengths (PubMed: 27634447). The accumulation of these peptides, particularly the aggregation-prone Aβ42, is a hallmark of Alzheimer's disease pathology and is thought to trigger neurodegeneration. Consequently, these enzymes have been major therapeutic targets for small-molecule inhibitors aimed at reducing Aβ burden in the brain. However, clinical development has been hindered by safety issues, such as the disruption of Notch signaling by gamma-secretase inhibitors and paradoxical cognitive decline in BACE inhibitor trials, highlighting the complexity of targeting these essential proteases (PubMed: 30305516). Despite these setbacks, the pathway remains a central focus of research into the molecular mechanisms of dementia and potential disease-modifying therapies.

Other names

BACE1Beta-site APP cleaving enzyme 1Gamma-secretase complexPresenilin complexAmyloidogenic pathway enzymesAPP secretases

Inhibition of the sequential proteolytic cleavage of amyloid precursor protein (APP) by beta-secretase (BACE1) and the gamma-secretase complex to prevent the generation and accumulation of neurotoxic amyloid-beta (Aβ) peptides (PubMed: 27634447).