Amyloid-beta (Aβ) D7H mutation increases oligomeric Aβ42 and alters properties of Aβ-zinc/copper assemblies

PLoS One. 2012;7(4):e35807. doi: 10.1371/journal.pone.0035807. Epub 2012 Apr 30.


Amyloid precursor protein (APP) mutations associated with familial Alzheimer's disease (AD) usually lead to increases in amyloid β-protein (Aβ) levels or aggregation. Here, we identified a novel APP mutation, located within the Aβ sequence (Aβ(D7H)), in a Taiwanese family with early onset AD and explored the pathogenicity of this mutation. Cellular and biochemical analysis reveal that this mutation increased Aβ production, Aβ42/40 ratio and prolonged Aβ42 oligomer state with higher neurotoxicity. Because the D7H mutant Aβ has an additional metal ion-coordinating residue, histidine, we speculate that this mutation may promote susceptibility of Aβ to ion. When co-incubated with Zn(2+) or Cu(2+), Aβ(D7H) aggregated into low molecular weight oligomers. Together, the D7H mutation could contribute to AD pathology through a "double punch" effect on elevating both Aβ production and oligomerization. Although the pathogenic nature of this mutation needs further confirmation, our findings suggest that the Aβ N-terminal region potentially modulates APP processing and Aβ aggregation, and further provides a genetic indication of the importance of Zn(2+) and Cu(2+) in the etiology of AD.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism
  • Amino Acid Sequence
  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Peptides / genetics*
  • Amyloid beta-Protein Precursor / chemistry
  • Amyloid beta-Protein Precursor / genetics*
  • Aspartic Acid / chemistry
  • Aspartic Acid / genetics
  • Base Sequence
  • Cells, Cultured
  • Copper / chemistry*
  • Copper / metabolism
  • Female
  • HEK293 Cells
  • Histidine / chemistry
  • Histidine / genetics
  • Humans
  • Middle Aged
  • Molecular Sequence Data
  • Mutation
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics*
  • Polymerization
  • Taiwan
  • Zinc / chemistry*
  • Zinc / metabolism


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Peptide Fragments
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)
  • Aspartic Acid
  • Histidine
  • Copper
  • Zinc