Oral Treatment with the D-Enantiomeric Peptide D3 Improves the Pathology and Behavior of Alzheimer's Disease Transgenic Mice
Oral Treatment with the D-Enantiomeric Peptide D3 Improves the Pathology and Behavior of Alzheimer's Disease Transgenic Mice
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DOI：
10.1021/cn100057j
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发表时间：
2010-09-01
影响因子：
5
通讯作者：
Willbold, Dieter
中科院分区：
文献类型：
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作者：
Funke, Susanne Aileen;van Groen, Thomas;Willbold, Dieter
多项证据表明，淀粉样β-肽（Aβ）在阿尔茨海默病（AD）的发病机制中发挥着核心作用。不仅 A β 原纤维，而且特别是小的可溶性 A β 寡聚物都被怀疑是导致疾病发生和进展的主要有毒物质。本研究报告了 Aβ 靶向 D-对映体氨基酸肽 D3 的体外和体内特性。我们发现，除了斑块负荷和炎症减少之外，口服该肽还改善了 AD 转基因小鼠的认知表现。此外，我们提供了体外数据，阐明了观察到的 D3 体内活性的潜在机制。这些数据表明，D3 会沉淀有毒的 Aβ 物质，并将其转化为非淀粉样蛋白形成、非纤维状和无毒的聚集体，而不会增加单体 Aβ 的浓度。因此，D3 发挥了一种有趣且新颖的作用机制，可以消除有毒的 Aβ 寡聚体，从而支持它们在 AD 发生和进展中的决定性作用。
Several lines of evidence suggest that the amyloid-beta-peptide (A beta) plays a central role in the pathogenesis of Alzheimer's disease (AD). Not only A beta fibrils but also small soluble A beta oligomers in particular are suspected to be the major toxic species responsible for disease development and progression. The present study reports on in vitro and in vivo properties of the A beta targeting D-enantiomeric amino acid peptide D3. We show that next to plaque load and inflammation reduction, oral application of the peptide improved the cognitive performance of AD transgenic mice. In addition, we provide in vitro data elucidating the potential mechanism underlying the observed in vivo activity of D3. These data suggest that D3 precipitates toxic A beta species and converts them into nonamyloidogenic, nonfibrillar, and nontoxic aggregates without increasing the concentration of monomeric A beta. Thus, D3 exerts an interesting and novel mechanism of action that abolishes toxic A beta oligomers and thereby supports their decisive role in AD development and progression.