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

The Amyloid precursor protein (APP) processing pathway is a critical metabolic sequence in the central nervous system that regulates the production of amyloid-beta (Aβ) peptides [1]. In the amyloidogenic route, APP is sequentially cleaved by beta-site APP cleaving enzyme 1 (BACE1) and the gamma-secretase complex, releasing Aβ isoforms such as Aβ40 and the highly neurotoxic Aβ42 [2]. The accumulation and aggregation of Aβ42 into oligomers and insoluble plaques are hallmark features of Alzheimer's disease, leading to progressive synaptic dysfunction and neurodegeneration [3]. Conversely, the non-amyloidogenic pathway involves alpha-secretase cleavage within the Aβ domain, which prevents the formation of toxic peptides and releases neuroprotective fragments [1]. Therapeutic interventions targeting this pathway have historically focused on small-molecule inhibitors of BACE1 or gamma-secretase to reduce Aβ production, though many of these agents failed in clinical trials due to lack of efficacy or off-target toxicities, such as the inhibition of Notch signaling [4]. Modern pharmacological approaches have shifted toward gamma-secretase modulators (GSMs) and monoclonal antibodies designed to facilitate the clearance of existing Aβ aggregates from the brain [3][5]. Monitoring the products of this pathway via cerebrospinal fluid or plasma biomarkers is essential for patient selection and evaluating the efficacy of disease-modifying therapies in neurodegenerative disorders [2]. Sources: [1] UniProt (P05067); [2] Molecular Psychiatry (PMID: 33536588); [3] Nature Reviews Neurology (PMID: 30612835); [4] Biochemical Pharmacology (PMID: 31063651); [5] FDA Leqembi Prescribing Information.

Other names

Amyloidogenic pathwayAβ production pathwayAPP proteolytic processingBeta-amyloid cascadeAβ42 production pathway

Inhibition of beta-site APP cleaving enzyme 1 (BACE1), inhibition of the gamma-secretase complex, modulation of gamma-secretase cleavage specificity, and monoclonal antibody-mediated clearance of amyloid-beta aggregates.