Amyloid precursor protein (APP) processing pathway (APP processing pathway)

The Amyloid Precursor Protein (APP) processing pathway is a series of proteolytic events that determine the metabolic fate of APP, a protein essential for synaptic formation and repair (UniProt P05067). In the non-amyloidogenic pathway, APP is cleaved by alpha-secretase (primarily ADAM10), precluding the formation of the amyloid-beta (Aβ) peptide (O'Brien & Wong, 2011). The amyloidogenic pathway, however, involves sequential cleavage by beta-site APP cleaving enzyme 1 (BACE1) and the gamma-secretase complex, which releases Aβ peptides that can aggregate into neurotoxic plaques (Haass et al., 2012). This pathway is the primary focus of the "amyloid hypothesis" in Alzheimer's disease, where an imbalance between Aβ production and clearance leads to neurodegeneration (Hardy & Selkoe, 2002). Therapeutic efforts have targeted this pathway through BACE1 inhibitors like verubecestat and gamma-secretase inhibitors like semagacestat, though many failed due to toxicity or lack of efficacy (Panza et al., 2019). Recent successes involve monoclonal antibodies such as lecanemab and aducanumab, which target the Aβ products of this pathway to facilitate their clearance from the brain (van Dyck et al., 2023). Safety concerns for drugs affecting this pathway include Amyloid-Related Imaging Abnormalities (ARIA) and potential interference with other physiological substrates like Notch (Sperling et al., 2011).

Other names

APP metabolismAmyloidogenic pathwayNon-amyloidogenic pathwayβ-amyloid precursor protein processing

Beta-secretase inhibition, Gamma-secretase inhibition, Alpha-secretase activation, Amyloid-beta aggregation inhibition, Monoclonal antibody-mediated amyloid clearance