title: Amyloid β-Protein Assembly: Differential Effects of the Protective A2T Mutation and Recessive A2V Familial Alzheimer's Disease Mutation.
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.
authors.affiliation: Department of Chemistry and Biochemistry, University of California , Santa Barbara, California 93106, United States.
authors.forename: Xueyun
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Chemistry and Biochemistry, University of California , Santa Barbara, California 93106, United States.
authors.forename: Deyu
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Neurology, David Geffen School of Medicine, Molecular Biology Institute and Brain Research Institute, University of California Los Angeles , Los Angeles, California 90095, United States.
authors.forename: Robin
authors.initials: R
authors.lastname: Roychaudhuri
authors.affiliation: Department of Neurology, David Geffen School of Medicine, Molecular Biology Institute and Brain Research Institute, University of California Los Angeles , Los Angeles, California 90095, United States.
authors.forename: David B
authors.initials: DB
authors.lastname: Teplow
authors.affiliation: Department of Chemistry and Biochemistry, University of California , Santa Barbara, California 93106, United States.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bowers
mesh_terms: D000409:Alanine / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics*; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics* / Q000648:ultrastructure; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D013058:Mass Spectrometry; D046529:Microscopy, Electron, Transmission; D009154:Mutation / Q000235:genetics*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics; D017433:Protein Structure, Secondary; D013912:Threonine / Q000235:genetics; D014633:Valine / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D013912:Threonine; D014633:Valine; D000409:Alanine
keywords: A2T; A2V; Amyloid β-protein; familial Alzheimer’s disease; ion mobility spectrometry; mass spectrometry; oligomerization