Amyloid precursor protein processing factors (APP processing factors) (APP processing factors)

Amyloid precursor protein (APP) processing factors are a group of enzymes and associated proteins that regulate the proteolytic cleavage of APP into various peptide fragments (O'Brien & Wong, 2011, Nature Reviews Neuroscience). The most clinically relevant pathway is the amyloidogenic pathway, where APP is sequentially cleaved by beta-secretase (BACE1) and the gamma-secretase complex to generate amyloid-beta (Aβ) peptides (Vassar et al., 1999, Science). These Aβ peptides, particularly Aβ42, are prone to aggregation and form the extracellular plaques that are a hallmark of Alzheimer's disease pathology (Selkoe & Hardy, 2016, EMBO Molecular Medicine). Conversely, the non-amyloidogenic pathway involves alpha-secretase (ADAM10), which cleaves APP within the Aβ sequence, thereby preventing the formation of toxic amyloid species (Kuhn et al., 2010, EMBO Journal). Therapeutic interventions have historically targeted these processing factors to reduce the amyloid burden in the brain (Panza et al., 2019, Nature Reviews Neurology). While BACE1 and gamma-secretase inhibitors were developed to halt Aβ production, many failed in clinical trials due to adverse effects like Notch pathway interference or a lack of cognitive improvement (De Strooper, 2003, Neuron). Understanding the precise regulation of these processing factors remains critical for developing next-generation neuroprotective therapies.

Other names

APP secretasesAmyloidogenic pathway enzymesBeta-amyloid processing machinerySecretase complex

Inhibition of beta-secretase (BACE1) or gamma-secretase to reduce the production of amyloid-beta peptides; modulation of secretase activity to favor non-amyloidogenic processing of the amyloid precursor protein (APP).