Amyloid precursor protein processing pathway (APP processing pathway)

The Amyloid precursor protein (APP) processing pathway, also known as the Aβ-related enzymes and processing axis, is a complex proteolytic system that regulates the production and degradation of amyloid-beta (Aβ) peptides. This axis involves the competing activities of α-secretase (ADAM10), which initiates the non-amyloidogenic pathway, and β-secretase (BACE1) followed by γ-secretase, which drive the amyloidogenic production of neurotoxic Aβ species. The balance of this axis is further maintained by Aβ-degrading enzymes such as neprilysin and insulin-degrading enzyme, which clear Aβ from the brain. Dysregulation of this processing axis is a central driver of Alzheimer's disease pathology, leading to the accumulation of Aβ plaques and subsequent neurodegeneration. Therapeutic strategies targeting this axis have primarily focused on BACE1 and γ-secretase inhibition, though these have faced significant clinical hurdles due to off-target effects and safety concerns. Recent research also explores the activation of α-secretase and the enhancement of degrading enzymes to restore Aβ homeostasis.

Other names

Aβ-related enzymes and processing axisAmyloid-beta processing axisAmyloidogenic pathwayNon-amyloidogenic pathwaySecretase processing of APPAβ metabolic pathway

Modulation of the proteolytic cleavage of amyloid precursor protein (APP) by inhibiting β-secretase (BACE1) or γ-secretase to reduce Aβ production, or by activating α-secretase (ADAM10) to promote the non-amyloidogenic pathway. It also includes the clearance of Aβ products via enzymatic degradation or antibody-mediated removal.