Positive Allosteric Modulators of SERCA Pump Restore Dendritic Spines and Rescue Long-Term Potentiation Defects in Alzheimer's Disease Mouse Model.
Positive Allosteric Modulators of SERCA Pump Restore Dendritic Spines and Rescue Long-Term Potentiation Defects in Alzheimer's Disease Mouse Model.
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DOI：
10.3390/ijms241813973
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发表时间：
2023-09-12
影响因子：
5.6
通讯作者：
Bezprozvanny, Ilya
中科院分区：
文献类型：
--
作者：
Rakovskaya, Anastasiya;Erofeev, Alexander;Vinokurov, Egor;Pchitskaya, Ekaterina;Dahl, Russell;Bezprozvanny, Ilya
关键词：
阿尔茨海默病（AD）是一种影响记忆形成和存储过程的神经退行性疾病。神经元钙 (Ca2+) 失调已被确定为 AD 的关键致病事件之一，并且有人建议稳定 Ca2+ 神经元信号传导的药物可以作为 AD 的疾病缓解剂。在之前的研究中，我们证明了肌浆/内质网 Ca2+ ATP 酶 (SERCA) 泵的正变构调节剂 (PAM) 可能充当这样的 Ca2+ 稳定剂并表现出神经保护特性。在本研究中，我们评估了一组新型 SERCA PAM 药物对 HEK293T 细胞系细胞质中 Ca2+ 提取率的影响，对正常条件和淀粉样蛋白毒性条件下原代海马神经元树突棘形态参数的影响，以及对来自 5xFAD 转基因小鼠 AD 模型的切片的长期增强作用的影响。几种 SERCA PAM 化合物表现出神经保护特性，其中化合物 NDC-9009 显示出最佳效果。这项研究的结果支持这样的假设：SERCA 泵是 AD 治疗的潜在治疗靶点，而 NDC-9009 是一种有前途的先导分子，可用于开发 AD 疾病缓解剂。
Alzheimer’s disease (AD) is a neurodegenerative disorder that affects memory formation and storage processes. Dysregulated neuronal calcium (Ca2+) has been identified as one of the key pathogenic events in AD, and it has been suggested that pharmacological agents that stabilize Ca2+ neuronal signaling can 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 and exhibit neuroprotective properties. In the present study, we evaluated effects of a set of novel SERCA PAM agents on the rate of Ca2+ extraction from the cytoplasm of the HEK293T cell line, on morphometric parameters of dendritic spines of primary hippocampal neurons in normal conditions and in conditions of amyloid toxicity, and on long-term potentiation in slices derived from 5xFAD transgenic mice modeling AD. Several SERCA PAM compounds demonstrated neuroprotective properties, and the compound NDC-9009 showed the best results. The findings in this study support the hypothesis that the SERCA pump is a potential therapeutic target for AD treatment and that NDC-9009 is a promising lead molecule to be used in the development of disease-modifying agents for AD.
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影响因子：
--
作者：
Cornea RL;Gruber SJ;Lockamy EL;Muretta JM;Jin D;Chen J;Dahl R;Bartfai T;Zsebo KM;Gillispie GD;Thomas DD
通讯作者：
Thomas DD
影响因子：
6
作者：
Chami M;Checler F
通讯作者：
Checler F
影响因子：
7.3
作者：
Gobbini, Mauro;Armaroli, Silvia;Cerri, Alberto
通讯作者：
Cerri, Alberto
影响因子：
15.1
作者：
Popugaeva E;Pchitskaya E;Speshilova A;Alexandrov S;Zhang H;Vlasova O;Bezprozvanny I
通讯作者：
Bezprozvanny I
影响因子：
56.9
作者：
FREY, U;HUANG, YY;KANDEL, ER
通讯作者：
KANDEL, ER