A multifunctional therapeutic approach to disease modification in multiple familial mouse models and a novel sporadic model of Alzheimer's disease.
A multifunctional therapeutic approach to disease modification in multiple familial mouse models and a novel sporadic model of Alzheimer's disease.
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DOI：
10.1186/s13024-016-0103-6
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发表时间：
2016-04-29
影响因子：
15.1
通讯作者：
Thatcher GR
中科院分区：
文献类型：
--
作者：
Luo J;Lee SH;VandeVrede L;Qin Z;Ben Aissa M;Larson J;Teich AF;Arancio O;D'Souza Y;Elharram A;Koster K;Tai LM;LaDu MJ;Bennett BM;Thatcher GR
单独靶向淀粉样蛋白-β病理学的临床失败表明迫切需要替代阿尔茨海默病（AD）治疗策略。在大量AD患者中报告的混合病理学需要多功能药物方法。由于cAMP反应元件结合蛋白（CREB）的激活在突触强化和记忆形成中起着至关重要的作用，我们重新设计了一种具有已知神经保护和抗炎活性的临床药物来激活CREB，并在4种不同的AD小鼠模型中验证了这种新型多功能药物NMZ。在三种家族性AD小鼠模型和一种散发性AD模型中测试了NMZ。在3 × Tg海马脑片中，NMZ恢复LTP。在体内，在所有具有稳健认知缺陷的动物模型中，NMZ改善了记忆。NMZ治疗降低了APP/PS1和3 × Tg转基因小鼠中Aβ的神经毒性形式，同时还恢复了3 × Tg小鼠中的神经元可塑性生物标志物。在EFAD小鼠中，主要遗传性AD风险因子hAPOE 4的掺入并未减弱有益的药物作用。在一种新的散发性小鼠模型中，该模型表现出在不存在任何家族性AD突变的情况下由加速氧化应激引起的AD样病理学，经口给予NMZ减弱了标志性AD病理学，并恢复了突触和神经元功能的生物标志物。由NMZ体现的多功能方法在AD小鼠模型中获得成功，包括Aβ病理学（APP/PS1）、tau病理学（3xTg）和APOE 4（AD的主要人类遗传风险因子（EFAD））。在散发性AD（Aldh 2 −/−）的新模型中观察到的疗效表明，治疗方法不仅限于罕见的家族性AD基因突变。多功能药物NMZ并非直接设计用于靶向Aβ和tau病理学;然而，这种标志性病理学的减弱表明该方法是AD和混合病理学痴呆的一种非常有前途的疾病改善策略。
Clinical failures singularly targeting amyloid-β pathology indicate a critical need for alternative Alzheimer’s disease (AD) therapeutic strategies. The mixed pathology reported in a large population of AD patients demands a multifunctional drug approach. Since activation of cAMP response element binding protein (CREB) plays a crucial role in synaptic strengthening and memory formation, we retooled a clinical drug with known neuroprotective and anti-inflammatory activity to activate CREB, and validated this novel multifunctional drug, NMZ, in 4 different mouse models of AD. NMZ was tested in three mouse models of familial AD and one model of sporadic AD. In 3 × Tg hippocampal slices, NMZ restored LTP. In vivo, memory was improved with NMZ in all animal models with robust cognitive deficits. NMZ treatment lowered neurotoxic forms of Aβ in both APP/PS1 and 3 × Tg transgenic mice while also restoring neuronal plasticity biomarkers in the 3 × Tg mice. In EFAD mice, incorporation of the major genetic AD risk factor, hAPOE4, did not mute the beneficial drug effects. In a novel sporadic mouse model that manifests AD-like pathology caused by accelerated oxidative stress in the absence of any familial AD mutation, oral administration of NMZ attenuated hallmark AD pathology and restored biomarkers of synaptic and neuronal function. The multifunctional approach, embodied by NMZ, was successful in mouse models of AD incorporating Aβ pathology (APP/PS1), tau pathology (3xTg), and APOE4, the major human genetic risk factor for AD (EFAD). The efficacy observed in a novel model of sporadic AD (Aldh2−/−) demonstrates that the therapeutic approach is not limited to rare, familial AD genetic mutations. The multifunctional drug, NMZ, was not designed directly to target Aβ and tau pathology; however, the attenuation of this hallmark pathology suggests the approach to be a highly promising, disease-modifying strategy for AD and mixed pathology dementia.