Residues at P2-P1 positions of ε- and ζ-cleavage sites are important in formation of β-amyloid peptide

NEUROBIOLOGY OF DISEASE

卷:36

Article

Tan, Jianxin¹  Mao, Guozhang¹  Cui, Mei-Zhen¹  Lamb, Bruce²  Sy, Man-Sun³  Xu, Xuemin¹ 

[1] Univ Tennessee, Coll Vet Med, Dept Pathobiol, Knoxville, TN 37996 USA

[2] Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA

[3] Cleveland Clin Fdn, Lerner Res Inst, Dept Neurosci, Cleveland, OH 44195 USA

关键词: Alzheimer's disease;    beta-amyloid;    gamma-secretase;    APP;    Intramembrame processing;   

DOI  :  10.1016/j.nbd.2009.08.010

来源: Elsevier

【 摘 要 】

Most of the Alzheimer's disease (AD)-linked mutations in amyloid precursor protein (APP), which cause abnormal production of beta-amyloid (A beta), 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 A beta 49 and the zeta-cleavage site at A beta 46, aromatic amino acids caused a strong reduction in total A beta. On the other hand, residues with a long side chain caused a decrease in A beta(40) and a concomitant increase in A beta(42) and A beta(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 A beta 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. (C) 2009 Elsevier Inc. All rights reserved.

【 授权许可】

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