Intracellular domain generation of amyloid precursor protein by epsilon-cleavage depends on C-terminal fragment by alpha-secretase cleavage.
A significant accumulation of Abeta is major pathological feature in the brain in patients with Alzheimer's disease (AD). Amyloid precursor protein (APP) is cleaved by alpha- and beta-secretase, resulting in secretion of extracellular domain. Then the remaining membrane-anchored C-terminal fragments (CTFalpha or CTFbeta) are cleaved by gamma-secretase. Therefore, Abeta is derived from APP by sequential proteolytic processing involving 2 proteases, called beta- and gamma-secretase. Gamma-secretase cleavage results in the generation of the APP intracellular domain (AICD), as well as Abeta. Recently, AICD is generated by epsilon-cleavage site near the cytoplasmic membrane boundary of APP, not by gamma-cleavage site in the middle of transmembrane domain. We show that elevated beta-secretase levels induced the increase in CTFbeta and Abeta generation and reduction of CTFalpha and AICD generation in vitro. Furthermore, elevated alpha-secretase levels induced an increase of AICD. The results suggest that generation of AICD by epsilon-cleavage depends on CTFalpha and that gamma- and epsilon-cleavage are differentially regulated.
Kume
Hideaki
H
Department of Moleculr Neurobiology, Tohoku University Graduate School of Medicine, Tokyo 156-8585, Japan.
Maruyama
Kei
K
Kametani
Fuyuki
F
D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D019556:COS Cells; D010450:Endopeptidases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D014162:Transfection
D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases