Comparison between the aggregation of human and rodent amyloid β-proteins in GM1 ganglioside clusters.
The abnormal deposition of amyloids by amyloid-β protein (Aβ) is a pathological hallmark of Alzheimer's disease (AD). Aged rodents rarely develop the characteristic lesions of the disease, which is different from the case in humans. Rodent Aβ (rAβ) differs from human Aβ (hAβ) only in the three substitutions of Arg to Gly, Tyr to Phe, and His to Arg at positions 5, 10, and 13, respectively. Understanding the reason why rodent Aβ does not form amyloids is important to revealing factors that cause the abnormal aggregation of Aβ under pathologic conditions. We have proposed that the binding of Aβ to membranes with ganglioside clusters plays an important role in the abnormal aggregation of Aβ. In this study, we compared hAβ and rAβ in terms of aggregation on neuronal cells, on raftlike model membranes, and in buffer. We found that rAβ formed amyloid fibrils similar to those of hAβ in buffer solution. In contrast, on cell membranes and raftlike membranes, hAβ formed toxic, mature amyloid fibrils, whereas rAβ produced less toxic protofibrils that were not stained by the amyloid-specific dye Congo red. Thus, our ganglioside cluster-mediated amyloidogenesis hypothesis explains the immunity of rodents from cerebral Aβ amyloid deposition, strengthening the importance of ganglioside clusters as a platform of abnormal Aβ deposition in the pathology of AD.
Graduate School of Pharmaceutical Sciences, Kyoto University , 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Hiroshi
H
Ueno
Takahiro
T
Yamaguchi
Saori
S
Fukunaga
Yuki
Y
Okada
Yoshiaki
Y
Yano
Masaru
M
Hoshino
Katsumi
K
Matsuzaki
D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000682:Amyloid / Q000737:chemistry / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D005677:G(M1) Ganglioside / Q000737:chemistry*; D006801:Humans; D021962:Membrane Microdomains / Q000737:chemistry; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D051381:Rats; D013045:Species Specificity; D017550:Spectroscopy, Fourier Transform Infrared
D000682:Amyloid; D016229:Amyloid beta-Peptides; D005677:G(M1) Ganglioside