アルツハイマー病アミロイドβタンパク質の凝集における 生体膜の役割

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  • Roles of Biomembranes in the Aggregation of Alzheimer’s Amyloid β-Protein
  • アルツハイマービョウ アミロイド ベータ タンパクシツ ノ ギョウシュウ ニ オケル セイタイ マク ノ ヤクワリ

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The conversion of soluble, nontoxic amyloid β-protein (Aβ) to aggregated, toxic Aβ rich in β-sheet structures by seeded polymerization is considered to be the key step in the development of Alzheimer’s disease. Accumulating evidence suggests that lipid rafts (microdomains) in membranes mainly composed of sphingolipids (gangliosides and sphingomyelin) and cholesterol play a pivotal role in this process. Our model membrane studies revealed the following mechanism. Soluble Aβ with unordered structures specifically binds to raft-like membranes containing a ganglioside cluster, the formation of which is facilitated by cholesterol. The membrane-bound Aβ forms an α-helix-rich structure at lower densities. At higher densities, Aβ undergoes a conformational transition to a β-sheet-rich structure that can serve as a seed for amyloid fibril formation. This model was confirmed in cellar level using rat pheochromocytoma PC12 cells. Fourier-transform infrared spectroscopic and electron micrographic studies revealed that the structures of Aβ fibrils formed in solution and lipid rafts are different. The fibrilization can be inhibited by small organic compounds and biocompatible nanogels.

収録刊行物

  • 膜

    膜 32 (4), 185-189, 2007

    日本膜学会

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