Amyloid β-Protein Assembly: Differential Effects of the Protective A2T Mutation and Recessive A2V Familial Alzheimer's Disease Mutation

Xueyun Zheng, Deyu Liu, Robin Roychaudhuri, David B. Teplow, Michael T. Bowers

Research output: Contribution to journalArticle

Abstract

Oligomeric states of the amyloid β-protein (Aβ) appear to be causally related to Alzheimer's disease (AD). Recently, two familial mutations in the amyloid precursor protein gene have been described, both resulting in amino acid substitutions at Ala2 (A2) within Aβ. An A2V mutation causes autosomal recessive early onset AD. Interestingly, heterozygotes enjoy some protection against development of the disease. An A2T substitution protects against AD and age-related cognitive decline in non-AD patients. Here, we use ion mobility-mass spectrometry (IM-MS) to examine the effects of these mutations on Aβ assembly. These studies reveal different assembly pathways for early oligomer formation for each peptide. A2T Aβ42 formed dimers, tetramers, and hexamers, but dodecamer formation was inhibited. In contrast, no significant effects on Aβ40 assembly were observed. A2V Aβ42 also formed dimers, tetramers, and hexamers, but it did not form dodecamers. However, A2V Aβ42 formed trimers, unlike A2T or wild-type (wt) Aβ42. In addition, the A2V substitution caused Aβ40 to oligomerize similar to that of wt Aβ42, as evidenced by the formation of dimers, tetramers, hexamers, and dodecamers. In contrast, wt Aβ40 formed only dimers and tetramers. These results provide a basis for understanding how these two mutations lead to, or protect against, AD. They also suggest that the Aβ N-terminus, in addition to the oft discussed central hydrophobic cluster and C-terminus, can play a key role in controlling disease susceptibility.

Original languageEnglish (US)
Pages (from-to)1732-1740
Number of pages9
JournalACS Chemical Neuroscience
Volume6
Issue number10
DOIs
StatePublished - Oct 21 2015
Externally publishedYes

Keywords

  • A2T
  • A2V
  • Amyloid β-protein
  • familial Alzheimer's disease
  • ion mobility spectrometry
  • mass spectrometry
  • oligomerization

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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