Inhibitors of amyloid beta-protein aggregation mediated by GM1-containing raft-like membranes.
The aggregation (fibril formation) of amyloid beta-protein (Abeta) is considered to be a crucial step in the etiology of Alzheimer's disease (AD). The inhibition of Abeta aggregation and/or decomposition of fibrils formed in aqueous solution by small compounds have been studied extensively for the prevention and treatment of AD. However, recent studies suggest that Abeta aggregation also occurs in lipid rafts mediated by a cluster of monosialoganglioside GM1. This study examined the effects of representative compounds on Abeta aggregation and fibril destabilization in the presence of GM1-containing raft-like liposomes. Among the compounds tested, nordihydroguaiaretic acid (NDGA), rifampicin (RIF), tannic acid (TA), and quercetin (QUE) showed strong fibrillization inhibitory activity. NDGA and RIF inhibited the binding of Abeta to GM1 liposomes by competitively binding to the membranes and/or direct interaction with Abeta in solution, thus at least partly preventing fibrils from forming. Coincubation of Abeta with NDGA, RIF, and QUE in the presence of GM1 liposomes resulted in elongate particles, whereas the presence of TA yielded protofibrillar structures. TA and RIF also destabilized fibrils. The most potent NDGA prevented Abeta-induced toxicity in PC12 cells by inhibiting Abeta accumulation. Furthermore, a comparison of the inhibitory effects of various compounds between aqueous-phase and GM1-mediated aggregation of Abeta suggested that the two aggregation processes are not identical.
Matsuzaki
Katsumi
K
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. katsumim@pharm.kyoto-u.ac.jp
Noguch
Taeko
T
Wakabayashi
Masaki
M
Ikeda
Keisuke
K
Okada
Takuma
T
Ohashi
Yumiko
Y
Hoshino
Masaru
M
Naiki
Hironobu
H
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000378:metabolism / Q000494:pharmacology; D005677:G(M1) Ganglioside / Q000737:chemistry* / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry; D008563:Membrane Lipids / Q000737:chemistry; D021962:Membrane Microdomains / Q000737:chemistry* / Q000378:metabolism; D016716:PC12 Cells; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D010636:Phenols / Q000378:metabolism / Q000494:pharmacology; D059808:Polyphenols; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation / Q000187:drug effects; D011489:Protein Denaturation / Q000187:drug effects; D051381:Rats
D016229:Amyloid beta-Peptides; D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D005419:Flavonoids; D008081:Liposomes; D008563:Membrane Lipids; D010446:Peptide Fragments; D010636:Phenols; D059808:Polyphenols; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D005677:G(M1) Ganglioside