Positive Allosteric Modulator of SERCA Pump NDC-1173 Exerts Beneficial Effects in Mouse Model of Alzheimer's Disease.
Positive Allosteric Modulator of SERCA Pump NDC-1173 Exerts Beneficial Effects in Mouse Model of Alzheimer's Disease.
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DOI：
10.3390/ijms241311057
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发表时间：
2023-07-04
影响因子：
5.6
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阿尔茨海默病（AD）是一种不可逆的神经退行性疾病，影响着全世界数百万人。AD没有治愈方法，并且AD领域的大多数药物开发努力都集中在基于“淀粉样蛋白级联假说”靶向淀粉样蛋白途径。然而，除了淀粉样蛋白途径之外，大量证据还指出神经元钙（Ca 2+）信号传导失调是AD中的关键致病事件之一，并且已经提出稳定神经元Ca 2+信号传导的药理学试剂可以作为AD中的疾病修饰剂。在以前的研究中，我们证明了Sarco/内质网Ca 2 + ATP酶（SERCA）泵的正变构调节剂（PAM）可能作为这样的Ca 2+稳定剂。在本研究中，我们报告了一种新的SERCA PAM剂，化合物NDC-1173的开发。为了测试该化合物的有效性，我们用APP/PS1转基因AD小鼠模型进行了行为研究。我们还评估了该化合物对APP/PS1小鼠海马中内质网（ER）应激基因表达的影响。本研究的结果支持以下假设：SERCA泵是一种潜在的新型治疗药物靶标，NDC-1173是开发AD疾病修饰剂的有前途的先导分子。
Alzheimer’s disease (AD) is an irreversible neurodegenerative disease that affects millions of people worldwide. AD does not have a cure and most drug development efforts in the AD field have been focused on targeting the amyloid pathway based on the “amyloid cascade hypothesis”. However, in addition to the amyloid pathway, substantial evidence also points to dysregulated neuronal calcium (Ca2+) signaling as one of the key pathogenic events in AD, and it has been proposed that pharmacological agents that stabilize neuronal Ca2+ signaling may act as disease-modifying agents in AD. In previous studies, we demonstrated that positive allosteric regulators (PAMs) of the Sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) pump might act as such Ca2+ stabilizing agents. In the present study, we report the development of a novel SERCA PAM agent, compound NDC-1173. To test the effectiveness of this compound, we performed behavioral studies with the APP/PS1 transgenic AD mouse model. We also evaluated effects of this compound on expression of endoplasmic reticulum (ER) stress genes in the hippocampus of APP/PS1 mice. The results of this study support the hypothesis that the SERCA pump is a potential novel therapeutic drug target and that NDC-1173 is a promising lead molecule for developing disease-modifying agents in AD.