論文

査読有り
2011年4月

Two Distinct Amyloid beta-Protein (A beta) Assembly Pathways Leading to Oligomers and Fibrils Identified by Combined Fluorescence Correlation Spectroscopy, Morphology, and Toxicity Analyses

JOURNAL OF BIOLOGICAL CHEMISTRY
  • Satoko Matsumura
  • ,
  • Keiko Shinoda
  • ,
  • Mayumi Yamada
  • ,
  • Satoshi Yokojima
  • ,
  • Masafumi Inoue
  • ,
  • Takayuki Ohnishi
  • ,
  • Tetsuya Shimada
  • ,
  • Kazuya Kikuchi
  • ,
  • Dai Masui
  • ,
  • Shigeki Hashimoto
  • ,
  • Michio Sato
  • ,
  • Akane Ito
  • ,
  • Manami Akioka
  • ,
  • Shinsuke Takagi
  • ,
  • Yoshihiro Nakamura
  • ,
  • Kiyokazu Nemoto
  • ,
  • Yutaka Hasegawa
  • ,
  • Hisayoshi Takamoto
  • ,
  • Haruo Inoue
  • ,
  • Shinichiro Nakamura
  • ,
  • Yo-ichi Nabeshima
  • ,
  • David B. Teplow
  • ,
  • Masataka Kinjo
  • ,
  • Minako Hoshia

286
13
開始ページ
11555
終了ページ
11562
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1074/jbc.M110.181313
出版者・発行元
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Nonfibrillar assemblies of amyloid beta-protein (A beta) are considered to play primary roles in Alzheimer disease (AD). Elucidating the assembly pathways of these specific aggregates is essential for understanding disease pathogenesis and developing knowledge-based therapies. However, these assemblies cannot be monitored in vivo, and there has been no reliable in vitro monitoring method at low protein concentration. We have developed a highly sensitive in vitro monitoring method using fluorescence correlation spectroscopy (FCS) combined with transmission electron microscopy (TEM) and toxicity assays. Using A beta labeled at the N terminus or Lys(16), we uncovered two distinct assembly pathways. One leads to highly toxic 10-15-nm spherical A beta assemblies, termed amylospheroids (ASPDs). The other leads to fibrils. The first step in ASPD formation is trimerization. ASPDs of similar to 330 kDa in mass form from these trimers after 5 h of slow rotation. Up to at least 24 h, ASPDs remain the dominant structures in assembly reactions. Neurotoxicity studies reveal that the most toxic ASPDs are similar to 128 kDa (similar to 32-mers). In contrast, fibrillogenesis begins with dimer formation and then proceeds to formation of 15-40-nm spherical intermediates, from which fibrils originate after 15 h. Unlike ASPD formation, the Lys(16)-labeled peptide disturbed fibril formation because the A beta(16-20) region is critical for this final step. These differences in the assembly pathways clearly indicated that ASPDs are not fibril precursors. The method we have developed should facilitate identifying A beta assembly steps at which inhibition may be beneficial.

Web of Science ® 被引用回数 : 80

リンク情報
DOI
https://doi.org/10.1074/jbc.M110.181313
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/21292768
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000288797100065&DestApp=WOS_CPL
ID情報
  • DOI : 10.1074/jbc.M110.181313
  • ISSN : 0021-9258
  • PubMed ID : 21292768
  • Web of Science ID : WOS:000288797100065

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