Amyloid precursor protein compartmentalization restricts beta-amyloid production: therapeutic targets based on BACE compartmentalization.
Alzheimer's disease (AD) is defined by deposits of the 42-residue amyloid-beta peptide (Abeta42) in the brain. Abeta42 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. beta-secretase (BACE-1), an aspartyl protease, cleaves approx 10% of the APP in neuronal cells on the N-terminal side of Abeta to produce the C-terminal fragment (CTFbeta), which is cleaved by gamma-secretase to produce mostly Abeta of 40 residues (90%) and approx10% Abeta42. A third enzyme, alpha-secretase, cleaves APP after Abeta16 to secrete sAPPalpha and CTFalpha, the major metabolites of APP. Moreover, previous studies have demonstrated that phorbol esters stimulate processing of APP by alpha-secretase. Because alpha-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 alpha-secretase processing in a human neuroblastoma cell line does not increase the yield of Abeta, suggesting that the APP substrate targeted for alpha-secretase processing is not diverted to the BACE-1 pathway. However, when phorbol ester-induced alpha-secretase was similarly inhibited, we detected an increase in BACE-1 processing and AB yield. We explain these results compartmentalization of BACE-1 and alpha-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.
Medical University of South Carolina, Charleston, SC, 29425, USA.
Swetal
S
Gandhi
Lorenzo M
LM
Refolo
Kumar
K
Sambamurti
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000187:drug effects / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000187:drug effects / Q000378:metabolism; D002451:Cell Compartmentation / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000494:pharmacology; D010450:Endopeptidases / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010446:Peptide Fragments / Q000096:biosynthesis*; D010703:Phorbol Esters / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D022142:Secretory Vesicles / Q000187:drug effects / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004151:Dipeptides; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; C092152:N-((2-(hydroxyaminocarbonyl)methyl)-4-methylpentanoyl)-3-(2'-naphthyl)alanylalanine, 2-aminoethylamide; D010446:Peptide Fragments; D010703:Phorbol Esters; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein