Small molecule inhibitors of aggregation indicate that amyloid β oligomerization and fibrillization pathways are independent and distinct

被引:574
作者
Necula, Mihaela [1 ]
Kayed, Rakez [1 ]
Milton, Saskia [1 ]
Glabe, Charles G. [1 ]
机构
[1] Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA
关键词
D O I
10.1074/jbc.M608207200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Alzheimer disease is characterized by the abnormal aggregation of amyloid beta peptide into extracellular fibrillar deposits known as amyloid plaques. Soluble oligomers have been observed at early time points preceding fibril formation, and these oligomers have been implicated as the primary pathological species rather than the mature fibrils. A significant issue that remains to be resolved is whether amyloid oligomers are an obligate intermediate on the pathway to fibril formation or represent an alternate assembly pathway that may or may not lead to fiber formation. To determine whether amyloid beta oligomers are obligate intermediates in the fibrillization pathway, we characterized the mechanism of action of amyloid beta aggregation inhibitors in terms of oligomer and fibril formation. Based on their effects, the small molecules segregated into three distinct classes: compounds that inhibit oligomerization but not fibrillization, compounds that inhibit fibrillization but not oligomerization, and compounds that inhibit both. Several compounds selectively inhibited oligomerization at substoichiometric concentrations relative to amyloid beta monomer, with some active in the low nanomolar range. These results indicate that oligomers are not an obligate intermediate in the fibril formation pathway. In addition, these data suggest that small molecule inhibitors are useful for clarifying the mechanisms underlying protein aggregation and may represent potential therapeutic agents that target fundamental disease mechanisms.
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页码:10311 / 10324
页数:14
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共 106 条
  • [1] Early events in the fibrillation of monomeric insulin
    Ahmad, A
    Uversky, VN
    Hong, D
    Fink, AL
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (52) : 42669 - 42675
  • [2] Stimulation of insulin fibrillation by urea-induced intermediates
    Ahmad, A
    Millett, IS
    Doniach, S
    Uversky, VN
    Fink, AL
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (15) : 14999 - 15013
  • [3] Protofibrillar islet amyloid polypeptide permeabilizes synthetic vesicles by a pore-like mechanism that may be relevant to type II diabetes
    Anguiano, M
    Nowak, RJ
    Lansbury, PT
    [J]. BIOCHEMISTRY, 2002, 41 (38) : 11338 - 11343
  • [4] Pathway complexity of prion protein assembly into amyloid
    Baskakov, IV
    Legname, G
    Baldwin, MA
    Prusiner, SB
    Cohen, FE
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (24) : 21140 - 21148
  • [5] Amyloid β-protein (Aβ) assembly:: Aβ40 and Aβ42 oligomerize through distinct pathways
    Bitan, G
    Kirkitadze, MD
    Lomakin, A
    Vollers, SS
    Benedek, GB
    Teplow, DB
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (01) : 330 - 335
  • [6] In-situ atomic force microscopy study of β-amyloid fibrillization
    Blackley, HKL
    Sanders, GHW
    Davies, MC
    Roberts, CJ
    Tendler, SJB
    Wilkinson, MJ
    [J]. JOURNAL OF MOLECULAR BIOLOGY, 2000, 298 (05) : 833 - 840
  • [7] Cultured cell and transgenic mouse models for tau pathology linked to β-amyloid
    Bloom, GS
    Ren, K
    Glabe, CG
    [J]. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, 2005, 1739 (2-3): : 116 - 124
  • [8] Self-assembly of β-amyloid 42 is retarded by small molecular ligands at the stage of structural intermediates
    Bohrmann, B
    Adrian, M
    Dubochet, J
    Kuner, P
    Müller, F
    Huber, W
    Nordstedt, C
    Döbeli, H
    [J]. JOURNAL OF STRUCTURAL BIOLOGY, 2000, 130 (2-3) : 232 - 246
  • [9] Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases
    Bucciantini, M
    Giannoni, E
    Chiti, F
    Baroni, F
    Formigli, L
    Zurdo, JS
    Taddei, N
    Ramponi, G
    Dobson, CM
    Stefani, M
    [J]. NATURE, 2002, 416 (6880) : 507 - 511
  • [10] BURDICK D, 1992, J BIOL CHEM, V267, P546