Melatonin Reverses the Profibrillogenic Activity of Apolipoprotein E4 on the Alzheimer Amyloid A Peptide
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- 作者：Burkhard Poeggeler ; Leticia Miravalle ; Michael G. Zagorski ; Thomas Wisniewski ; Yau-Jan Chyan ; Yongbo Zhang ; Haiyan Shao ; Tara Bryant-Thomas ; Ruben Vidal ; Blas Frangione ; Jorge Ghiso ; and Miguel A. Pap
- 刊名：Biochemistry
- 出版年：2001
- 出版时间：December 11, 2001
- 年：2001
- 卷：40
- 期：49
- 页码：14995 - 15001
- 全文大小：155K
- 年卷期：v.40,no.49(December 11, 2001)
- ISSN：1520-4995
文摘
Inheritance of apoE4 is a strong risk factor for the development of late-onset sporadicAlzheimer's disease (AD). Several lines of evidence suggest that apoE4 binds to the Alzheimer A
proteinand, under certain experimental conditions, promotes formation of -sheet structures and amyloid fibrils.Deposition of amyloid fibrils is a critical step in the development of AD. We report here that addition ofmelatonin to A in the presence of apoE resulted in a potent isoform-specific inhibition of fibril formation,the extent of which was far greater than that of the inhibition produced by melatonin alone. This effectwas structure-dependent and unrelated to the antioxidant properties of melatonin, since it could bereproduced neither with the structurally related indole N-acetyl-5-hydroxytryptamine nor with theantioxidants ascorbate, 
-tocophenol, and PBN. The enhanced inhibitory effects of melatonin and apoEwere lost when bovine serum albumin was substituted for apoE. In addition, A in combination withapoE was highly neurotoxic (apoE4 > apoE3) to neuronal cells in culture, and this activity was alsoprevented by melatonin. These findings suggest that reductions in brain melatonin, which occur duringaging, may contribute to a proamyloidogenic microenvironment in the aging brain.
proteinand, under certain experimental conditions, promotes formation of -sheet structures and amyloid fibrils.Deposition of amyloid fibrils is a critical step in the development of AD. We report here that addition ofmelatonin to A in the presence of apoE resulted in a potent isoform-specific inhibition of fibril formation,the extent of which was far greater than that of the inhibition produced by melatonin alone. This effectwas structure-dependent and unrelated to the antioxidant properties of melatonin, since it could bereproduced neither with the structurally related indole N-acetyl-5-hydroxytryptamine nor with theantioxidants ascorbate, -tocophenol, and PBN. The enhanced inhibitory effects of melatonin and apoEwere lost when bovine serum albumin was substituted for apoE. In addition, A in combination withapoE was highly neurotoxic (apoE4 > apoE3) to neuronal cells in culture, and this activity was alsoprevented by melatonin. These findings suggest that reductions in brain melatonin, which occur duringaging, may contribute to a proamyloidogenic microenvironment in the aging brain.