Amyloid-β protein oligomerization and the importance of tetramers and dodecamers in the aetiology of Alzheimer's disease.
In recent years, small protein oligomers have been implicated in the aetiology of a number of important amyloid diseases, such as type 2 diabetes, Parkinson's disease and Alzheimer's disease. As a consequence, research efforts are being directed away from traditional targets, such as amyloid plaques, and towards characterization of early oligomer states. Here we present a new analysis method, ion mobility coupled with mass spectrometry, for this challenging problem, which allows determination of in vitro oligomer distributions and the qualitative structure of each of the aggregates. We applied these methods to a number of the amyloid-β protein isoforms of Aβ40 and Aβ42 and showed that their oligomer-size distributions are very different. Our results are consistent with previous observations that Aβ40 and Aβ42 self-assemble via different pathways and provide a candidate in the Aβ42 dodecamer for the primary toxic species in Alzheimer's disease.
Bernstein
Summer L
SL
Department of Chemistry & Biochemistry, University of California, Santa Barbara, California 93106-9510, USA.
Dupuis
Nicholas F
NF
Lazo
Noel D
ND
Wyttenbach
Thomas
T
Condron
Margaret M
MM
Bitan
Gal
G
Teplow
David B
DB
Shea
Joan-Emma
JE
Ruotolo
Brandon T
BT
Robinson
Carol V
CV
Bowers
Michael T
MT
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology; D006801:Humans; D013058:Mass Spectrometry; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology*; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D020033:Protein Isoforms; C075222:amyloid beta-protein (1-42)