Amyloid precursor protein compartmentalization restricts [beta]-amyloid production: Therapeutic targets based on BACE compartmentalization

• Published in: Journal of molecular neuroscience 2004-08, Vol.24 (1), p.137
• Main Authors: Gandhi, Swetal, Refolo, Lorenzo M, Sambamurti, Kumar
• Format: Article
• Language: English
• Subjects: Competition; Proteins
• ISSN: 0895-8696; 1559-1166
• DOI: 10.1385/JMN:24:1:137

Alzheimer's disease (AD) is defined by deposits of the 42-residue amyloid-β peptide (Aβ42) in the brain. Aβ42 is a minor metabolite of the amyloid precursor protein (APP), but its relative levels are increased by mutations on APP and presenilins 1 and 2 linked to familial AD. β-secretase (BACE-1), an aspartyl protease, cleaves approx 10% of the APP in neuronal cells on the N-terminal side of Aβ to produce the C-terminal fragment (CTFβ), which is cleaved by γ-secretase to produce mostly Aβ of 40 residues (90%) and approx10% Aβ42. A third enzyme, α-secretase, cleaves APP after Aβ16 to secrete sAPPα and CTFα, the major metabolites of APP. Moreover, previous studies have demonstrated that phorbol esters stimulate processing of APP by α-secretase. Because α-secretase and BACE-1 cleave APP within the secretory pathway, it is likely that the two enzymes compete for the APP substrate. This type of competition can explain the failure to saturate the minor BACE-1 pathway by overexpressing APP in the cell. In this study, we demonstrate that inhibition of constitutive α-secretase processing in a human neuroblastoma cell line does not increase the yield of Aβ, suggesting that the APP substrate targeted for α-secretase processing is not diverted to the BACE-1 pathway. However, when phorbol ester-induced α-secretase was similarly inhibited, we detected an increase in BACE-1 processing and AB yield. We explain these results compartmentalization of BACE-1 and α-secretase with processing depending on sorting of APP to the two compartments. The simplest explanation for the detection of competition between the two pathways upon phorbol ester stimulation is the partial failure of this compartmentalization by phorbol ester-induced release of secretory vesicles.[PUBLICATION ABSTRACT]