Selective PPAR-Delta/PPAR-Gamma Activation Improves Cognition in a Model of Alzheimer's Disease.
Selective PPAR-Delta/PPAR-Gamma Activation Improves Cognition in a Model of Alzheimer's Disease.
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工作背景：阿尔茨海默病（AD）与死亡率增加的持续增加的关联表明未满足的医疗需求和建立用于治疗潜力的新分子靶标的迫切需要。已知过氧化物酶体增殖物激活受体（PPAR）的激动剂调节体内的能量，并且已经显示出对阿尔茨海默病的积极作用。这类药物有三个成员（δ、γ和α），其中PPAR-gamma是研究最多的，因为这些药物激动剂为AD提供了希望，因为它们减少淀粉样蛋白β和tau病理，显示抗炎特性，并改善认知。然而，它们显示出较差的脑生物利用度，并且与对人类健康的几种不良副作用相关，从而限制了它们的临床应用。研究方法：我们已经通过计算机模拟开发了一系列新的PPAR-delta和PPAR-gamma激动剂，其中AU 9作为我们的先导化合物，其显示出选择性氨基酸相互作用，重点是避免PPAR-gamma AF 2配体结合结构域中的Tyr-473表位。结果如下：这种设计有助于避免当前PPAR-gamma激动剂的不需要的副作用，并改善行为缺陷和突触可塑性，同时降低3xTgAD动物中的淀粉样蛋白-β水平和炎症。结论：我们创新的PPAR-delta/gamma激动剂的计算机设计可能为这类AD激动剂提供新的前景。
Background: The continuously increasing association of Alzheimer’s disease (AD) with increased mortality rates indicates an unmet medical need and the critical need for establishing novel molecular targets for therapeutic potential. Agonists for peroxisomal proliferator activating receptors (PPAR) are known to regulate energy in the body and have shown positive effects against Alzheimer’s disease. There are three members of this class (delta, gamma, and alpha), with PPAR-gamma being the most studied, as these pharmaceutical agonists offer promise for AD because they reduce amyloid beta and tau pathologies, display anti-inflammatory properties, and improve cognition. However, they display poor brain bioavailability and are associated with several adverse side effects on human health, thus limiting their clinical application. Methods: We have developed a novel series of PPAR-delta and PPAR-gamma agonists in silico with AU9 as our lead compound that displays selective amino acid interactions focused upon avoiding the Tyr-473 epitope in the PPAR-gamma AF2 ligand binding domain. Results: This design helps to avoid the unwanted side effects of current PPAR-gamma agonists and improve behavioral deficits and synaptic plasticity while reducing amyloid-beta levels and inflammation in 3xTgAD animals. Conclusions: Our innovative in silico design of PPAR-delta/gamma agonists may offer new perspectives for this class of agonists for AD.
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影响因子：
4.3
作者：
Javonillo DI;Tran KM;Phan J;Hingco E;Kramár EA;da Cunha C;Forner S;Kawauchi S;Milinkeviciute G;Gomez-Arboledas A;Neumann J;Banh CE;Huynh M;Matheos DP;Rezaie N;Alcantara JA;Mortazavi A;Wood MA;Tenner AJ;MacGregor GR;Green KN;LaFerla FM
通讯作者：
LaFerla FM
DOI：
10.1007/978-1-4939-8994-2_10
发表时间：
2019-01-01
期刊：
PRE-CLINICAL MODELS
影响因子：
--
作者：
Kraeuter, Ann-Katrin;Guest, Paul C.;Sarnyai, Zoltan
通讯作者：
Sarnyai, Zoltan
影响因子：
4.7
作者：
Costello, DA;O'Leary, DM;Herron, CE
通讯作者：
Herron, CE
影响因子：
2.7
作者：
Gathiaka, Symon;Nanayakkara, Gayani;Amin, Rajesh H.
通讯作者：
Amin, Rajesh H.
影响因子：
4.2
作者：
Kariharan, Thiruchelvam;Nanayakkara, Gayani;Amin, Rajesh H.
通讯作者：
Amin, Rajesh H.