Effects of γ-secretase cleavage-region mutations on APP processing and Aβ formation

Interpretation with sequential cleavage and α-helical model

Jianxin Tan, Guozhang Mao, Mei Zhen Cui, Shin Chung Kang, Bruce Lamb, Boon Seng Wong, Man Sun Sy, Xuemin Xu

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Overwhelming evidence supports the amyloid hypothesis of Alzheimer's disease that stipulates that the relative level of the 42 amino acid β-amyloid peptide (Aβ42) in relationship to Aβ40 is critical to the pathogenesis of the disease. While it is clear that the multi-subunit gamma secretase is responsible for cleavage of the amyloid precursor protein (APP) into Aβ42 and Aβ40, the exact molecular mechanisms regulating the production of the various Aβ species remain elusive. To elucidate the underlying mechanisms, we replaced individual amino acid residues from positions 43 to 52 of Aβ with phenylalanine to examine the effects on the production of Aβ40 and Aβ42. All mutants, except for V50F, resulted in a decrease in total Aβ with a more prominent reduction in Aβ for residues 45, 48, and 51, following an every three residue repetition pattern. In addition, the mutations with the strongest reductions in total Aβ had the largest increases in the ratio of Aβ42/ Aβ40. Curiously, the T43F, V44F, and T48F mutations caused a striking decrease in the accumulation of membrane bound Aβ46, albeit by a different mechanism. Our data suggest that initial cleavage of APP at the ε site is crucial in the generation of Aβ. The implicated sequential cleavage and an α-helical model may lead to a better understanding of the γ-secretase-mediated APP processing and may also provide useful information for therapy and drug design aimed at altering Aβ production.

Original languageEnglish (US)
Pages (from-to)722-733
Number of pages12
JournalJournal of Neurochemistry
Volume107
Issue number3
DOIs
StatePublished - Nov 2008
Externally publishedYes

Fingerprint

Serum Amyloid A Protein
Amyloid Precursor Protein Secretases
Amyloid beta-Protein Precursor
Amyloid
Amino Acids
Mutation
Drug Design
Processing
Phenylalanine
Alzheimer Disease
Membranes
Pharmaceutical Preparations
Therapeutics
peptide A42

Keywords

  • Alzheimer's disease
  • Amyloid
  • Amyloid precursor protein processing

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Effects of γ-secretase cleavage-region mutations on APP processing and Aβ formation : Interpretation with sequential cleavage and α-helical model. / Tan, Jianxin; Mao, Guozhang; Cui, Mei Zhen; Kang, Shin Chung; Lamb, Bruce; Wong, Boon Seng; Sy, Man Sun; Xu, Xuemin.

In: Journal of Neurochemistry, Vol. 107, No. 3, 11.2008, p. 722-733.

Research output: Contribution to journalArticle

Tan, Jianxin ; Mao, Guozhang ; Cui, Mei Zhen ; Kang, Shin Chung ; Lamb, Bruce ; Wong, Boon Seng ; Sy, Man Sun ; Xu, Xuemin. / Effects of γ-secretase cleavage-region mutations on APP processing and Aβ formation : Interpretation with sequential cleavage and α-helical model. In: Journal of Neurochemistry. 2008 ; Vol. 107, No. 3. pp. 722-733.
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