Residues at P2-P1 positions of epsilon- and zeta-cleavage sites are important in formation of beta-amyloid peptide.
Most of the Alzheimer's disease (AD)-linked mutations in amyloid precursor protein (APP), which cause abnormal production of beta-amyloid (Abeta), are localized at the major beta-secretase-and gamma-secretase cleavage sites. In this study, using an APP-knockout mouse neuronal cell line, our data demonstrated that at the P2-P1 positions of the epsilon-cleavage site at Abeta49 and the zeta-cleavage site at Abeta46, aromatic amino acids caused a strong reduction in total Abeta. On the other hand, residues with a long side chain caused a decrease in Abeta(40) and a concomitant increase in Abeta(42) and Abeta(38). These findings indicate that the structures of the substituting residues at these key positions strongly determine the efficiency and preference of gamma-secretase-mediated APP processing, which determines the ratio of different secreted Abeta species, a crucial factor in the disease development. Our findings provide new insight into the mechanisms of gamma-secretase-mediated APP processing and, specifically, into why most AD-linked APP mutations are localized at major gamma-secretase cleavage sites. This information may contribute to the development of methods of prevention and treatment of Alzheimer's disease aimed at modulating gamma-secretase activity.
Tan
Jianxin
J
Department of Pathobiology, College of Veterinary Medicine, The University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA.
Mao
Guozhang
G
Cui
Mei-Zhen
MZ
Lamb
Bruce
B
Sy
Man-Sun
MS
Xu
Xuemin
X
D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D005998:Glycine / Q000737:chemistry; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010649:Phenylalanine / Q000737:chemistry; D058255:Protease Nexins; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics; D013912:Threonine / Q000737:chemistry; D014162:Transfection
C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D013912:Threonine; D010649:Phenylalanine; D053829:Amyloid Precursor Protein Secretases; D005998:Glycine