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 language | English (US) |
|---|---|
| Pages (from-to) | 453-460 |
| Number of pages | 8 |
| Journal | Neurobiology of Disease |
| Volume | 36 |
| Issue number | 3 |
| DOIs | |
| State | Published - Dec 2009 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - Residues at P2-P1 positions of e{open}- and ζ-cleavage sites are important in formation of β-amyloid peptide
AU - Tan, Jianxin
AU - Mao, Guozhang
AU - Cui, Mei Zhen
AU - Lamb, Bruce
AU - Sy, Man Sun
AU - Xu, Xuemin
PY - 2009/12
Y1 - 2009/12
N2 - 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.
AB - 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.
KW - β-amyloid
KW - γ-secretase
KW - Alzheimer's disease
KW - APP
KW - Intramembrane processing
UR - http://www.scopus.com/inward/record.url?scp=70350342277&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70350342277&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2009.08.010
DO - 10.1016/j.nbd.2009.08.010
M3 - Article
C2 - 19716417
AN - SCOPUS:70350342277
VL - 36
SP - 453
EP - 460
JO - Neurobiology of Disease
JF - Neurobiology of Disease
SN - 0969-9961
IS - 3
ER -