Residues at P2-P1 positions of e{open}- and ζ-cleavage sites are important in formation of β-amyloid peptide

Jianxin Tan, Guozhang Mao, Mei Zhen Cui, Bruce Lamb, Man Sun Sy, Xuemin Xu

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Most of the Alzheimer's disease (AD)-linked mutations in amyloid precursor protein (APP), which cause abnormal production of β-amyloid (Aβ), are localized at the major β-secretase-and γ-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 e{open}-cleavage site at Aβ49 and the ζ-cleavage site at Aβ46, aromatic amino acids caused a strong reduction in total Aβ. On the other hand, residues with a long side chain caused a decrease in Aβ40 and a concomitant increase in Aβ42 and Aβ38. These findings indicate that the structures of the substituting residues at these key positions strongly determine the efficiency and preference of γ-secretase-mediated APP processing, which determines the ratio of different secreted Aβ species, a crucial factor in the disease development. Our findings provide new insight into the mechanisms of γ-secretase-mediated APP processing and, specifically, into why most AD-linked APP mutations are localized at major γ-secretase cleavage sites. This information may contribute to the development of methods of prevention and treatment of Alzheimer's disease aimed at modulating γ-secretase activity.

Original languageEnglish (US)
Pages (from-to)453-460
Number of pages8
JournalNeurobiology of Disease
Volume36
Issue number3
DOIs
StatePublished - Dec 2009
Externally publishedYes

Fingerprint

Amyloid Precursor Protein Secretases
Amyloid
Peptides
Amyloid beta-Protein Precursor
Alzheimer Disease
Aromatic Amino Acids
Mutation
Knockout Mice
Cell Line

Keywords

  • β-amyloid
  • γ-secretase
  • Alzheimer's disease
  • APP
  • Intramembrane processing

ASJC Scopus subject areas

  • Neurology

Cite this

Residues at P2-P1 positions of e{open}- and ζ-cleavage sites are important in formation of β-amyloid peptide. / Tan, Jianxin; Mao, Guozhang; Cui, Mei Zhen; Lamb, Bruce; Sy, Man Sun; Xu, Xuemin.

In: Neurobiology of Disease, Vol. 36, No. 3, 12.2009, p. 453-460.

Research output: Contribution to journalArticle

Tan, Jianxin ; Mao, Guozhang ; Cui, Mei Zhen ; Lamb, Bruce ; Sy, Man Sun ; Xu, Xuemin. / Residues at P2-P1 positions of e{open}- and ζ-cleavage sites are important in formation of β-amyloid peptide. In: Neurobiology of Disease. 2009 ; Vol. 36, No. 3. pp. 453-460.
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