Caneus Julbert, Akanda Nesar, Rumsey John W, Guo Xiufang, Jackson Max, Long Christopher J, Sommerhage Frank, Georgieva Sanya, Kanaan Nicholas M, Morgan David, Hickman James J
NanoScience Technology Center University of Central Florida Orlando Florida USA.
Hesperos Inc. Orlando Florida USA.
Alzheimers Dement (N Y). 2020 May 27;6(1):e12029. doi: 10.1002/trc2.12029. eCollection 2020.
The quest to identify an effective therapeutic strategy for neurodegenerative diseases, such as mild congitive impairment (MCI) and Alzheimer's disease (AD), suffers from the lack of good human-based models. Animals represent the most common models used in basic research and drug discovery studies. However, safe and effective compounds identified in animal studies often translate poorly to humans, yielding unsuccessful clinical trials.
A functional in vitro assay based on long-term potentiation (LTP) was used to demonstrate that exposure to amyloid beta (Aβ) and tau oligomers, or brain extracts from AD transgenic mice led to prominent changes in human induced pluripotent stem cells (hiPSC)-derived cortical neurons, notably, without cell death.
Impaired information processing was demonstrated by treatment of neuron-MEA (microelectrode array) systems with the oligomers and brain extracts by reducing the effects of LTP induction. These data confirm the neurotoxicity of molecules linked to AD pathology and indicate the utility of this human-based system to model aspects of AD in vitro and study LTP deficits without loss of viability; a phenotype that more closely models the preclinical or early stage of AD.
In this study, by combining multiple relevant and important molecular and technical aspects of neuroscience research, we generated a new, fully human in vitro system to model and study AD at the preclinical stage. This system can serve as a novel drug discovery platform to identify compounds that rescue or alleviate the initial neuronal deficits caused by Aβ and/or tau oligomers, a main focus of clinical trials.
寻找针对神经退行性疾病（如轻度认知障碍[MCI]和阿尔茨海默病[AD]）的有效治疗策略，因缺乏良好的人体模型而受阻。动物是基础研究和药物发现研究中最常用的模型。然而，在动物研究中鉴定出的安全有效化合物往往难以转化应用于人类，导致临床试验失败。
基于长时程增强（LTP）的功能性体外试验被用于证明，暴露于β淀粉样蛋白（Aβ）和tau寡聚体，或AD转基因小鼠的脑提取物会导致人诱导多能干细胞（hiPSC）衍生的皮质神经元发生显著变化，特别是不会导致细胞死亡。
用寡聚体和脑提取物处理神经元-微电极阵列（MEA）系统，通过降低LTP诱导的作用，证明了信息处理受损。这些数据证实了与AD病理学相关分子的神经毒性，并表明这种基于人体的系统可用于在体外模拟AD的各个方面，并研究LTP缺陷而不丧失细胞活力；这种表型更接近模拟AD的临床前或早期阶段。
在本研究中，通过整合神经科学研究的多个相关且重要的分子和技术方面，我们构建了一个全新的、完全基于人体的体外系统，用于在临床前阶段模拟和研究AD。该系统可作为一个新型药物发现平台，以鉴定能够挽救或减轻由Aβ和/或tau寡聚体引起的初始神经元缺陷的化合物，这是临床试验的一个主要重点。
