Intrinsic determinants of neurotoxic aggregate formation by the amyloid beta peptide.
The extent to which proteins aggregate into distinct structures ranging from prefibrillar oligomers to amyloid fibrils is key to the pathogenesis of many age-related degenerative diseases. We describe here for the Alzheimer's disease-related amyloid beta peptide (Abeta) an investigation of the sequence-based determinants of the balance between the formation of prefibrillar aggregates and amyloid fibrils. We show that by introducing single-point mutations, it is possible to convert the normally harmless Abeta40 peptide into a pathogenic species by increasing its relative propensity to form prefibrillar but not fibrillar aggregates, and, conversely, to abolish the pathogenicity of the highly neurotoxic E22G Abeta42 peptide by reducing its relative propensity to form prefibrillar species rather than mature fibrillar ones. This observation can be rationalized by the demonstration that whereas regions of the sequence of high aggregation propensity dominate the overall tendency to aggregate, regions with low intrinsic aggregation propensities exert significant control over the balance of the prefibrillar and fibrillar species formed, and therefore play a major role in determining the neurotoxicity of the Abeta peptide.
Brorsson
Ann-Christin
AC
Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
Bolognesi
Benedetta
B
Tartaglia
Gian Gaetano
GG
Shammas
Sarah L
SL
Favrin
Giorgio
G
Watson
Ian
I
Lomas
David A
DA
Chiti
Fabrizio
F
Vendruscolo
Michele
M
Dobson
Christopher M
CM
Crowther
Damian C
DC
Luheshi
Leila M
LM
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000633:toxicity* / Q000648:ultrastructure; D000818:Animals; D052160:Benzothiazoles; D004331:Drosophila melanogaster / Q000187:drug effects; D007700:Kinetics; D008136:Longevity / Q000187:drug effects; D050505:Mutant Proteins / Q000737:chemistry / Q000633:toxicity / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics; D009498:Neurotoxins / Q000737:chemistry* / Q000633:toxicity*; D020836:Protein Structure, Quaternary; D013844:Thiazoles / Q000378:metabolism; D013997:Time Factors
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D050505:Mutant Proteins; D009498:Neurotoxins; D013844:Thiazoles; C009462:thioflavin T
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