LPYFDa Neutralizes Amyloid-β-Induced Memory Impairment and Toxicity
LPYFDa Neutralizes Amyloid-β-Induced Memory Impairment and Toxicity
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DOI：
10.3233/jad-2010-1297
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发表时间：
2010-01-01
影响因子：
4
通讯作者：
Eisel, Ulrich L. M.
中科院分区：
文献类型：
--
作者：
Granic, Ivica;Masman, Marcelo F.;Eisel, Ulrich L. M.
淀粉样蛋白- β (A β)肽的错误折叠、寡聚和聚集被广泛认为是阿尔茨海默病（AD）发病机制的中心事件。最近的研究已经确定可溶性A β低聚物是主要的致病因子，并提供证据表明这种低聚A β聚集体具有神经毒性，破坏突触可塑性，抑制长期增强。在对抗AD的战斗中，一个很有前途的治疗策略是应用短合成肽，这些肽被设计成与特定的A -区域结合，从而中和或干扰低聚A -物种的破坏性特性。在本研究中，我们在体外研究了淀粉样蛋白序列衍生的五肽LPYFDa的神经保护特性，以及它在体内对A β(42)诱导的学习缺陷的记忆保存能力。在体外，我们发现LPYFDa处理的培养神经元可以防止A β(42)诱导的细胞死亡。此外，在双侧海马内a β(42)注射后，LPYFDa在小鼠体内防止了情境恐惧条件反射范式下的记忆损伤。因此，我们首次证明了像LPYFDa这样的抗淀粉样蛋白肽可以通过恢复A β(42)寡聚物引起的学习缺陷来保护记忆。
Misfolding, oligomerization, and aggregation of the amyloid-beta (A beta) peptide is widely recognized as a central event in the pathogenesis of Alzheimer's disease (AD). Recent studies have identified soluble A beta oligomers as the main pathogenic agents and provided evidence that such oligomeric A beta aggregates are neurotoxic, disrupt synaptic plasticity, and inhibit long-term potentiation. A promising therapeutic strategy in the battle against AD is the application of short synthetic peptides which are designed to bind to specific A beta-regions thereby neutralizing or interfering with the devastating properties of oligomeric A beta species. In the present study, we investigated the neuroprotective properties of the amyloid sequence derived pentapeptide LPYFDa in vitro as well as its memory preserving capacity against A beta(42)-induced learning deficits in vivo. In vitro we showed that neurons in culture treated with LPYFDa are protected against A beta(42)-induced cell death. Moreover, in vivo LPYFDa prevented memory impairment tested in a contextual fear conditioning paradigm in mice after bilateral intrahippocampal A beta(42) injections. We thus showed for the first time that an anti-amyloid peptide like LPYFDa can preserve memory by reverting A beta(42) oligomer-induced learning deficits.