Liu Yajing, Yao Jinjing, Song Zhenpeng, Guo Wenting, Sun Bo, Wei Jinhong, Estillore John Paul, Back Thomas G, Chen S R Wayne
Department of Physiology and Pharmacology, Cumming School of Medicine, Libin Cardiovascular Institute, University of Calgary, Calgary, AB, Canada.
Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.
J Neurosci Res. 2021 Nov;99(11):2906-2921. doi: 10.1002/jnr.24936. Epub 2021 Aug 5.
Increasing evidence suggests that Alzheimer's disease (AD) progression is driven by a vicious cycle of soluble β-amyloid (Aβ)-induced neuronal hyperactivity. Thus, breaking this vicious cycle by suppressing neuronal hyperactivity may represent a logical approach to stopping AD progression. In support of this, we have recently shown that genetically and pharmacologically limiting ryanodine receptor 2 (RyR2) open time prevented neuronal hyperactivity, memory impairment, dendritic spine loss, and neuronal cell death in a rapid, early onset AD mouse model (5xFAD). Here, we assessed the impact of limiting RyR2 open time on AD-related deficits in a relatively late occurring, slow developing AD mouse model (3xTG-AD) that bears more resemblance (compared to 5xFAD) to that of human AD. Using behavioral tests, long-term potentiation recordings, and Golgi and Nissl staining, we found that the RyR2-E4872Q mutation, which markedly shortens the open duration of the RyR2 channel, prevented learning and memory impairment, defective long-term potentiation, dendritic spine loss, and neuronal cell death in the 3xTG-AD mice. Furthermore, pharmacologically shortening the RyR2 open time with R-carvedilol rescued these AD-related deficits in 3xTG mice. Therefore, limiting RyR2 open time may offer a promising, neuronal hyperactivity-targeted anti-AD strategy.
越来越多的证据表明，阿尔茨海默病（AD）的进展是由可溶性β淀粉样蛋白（Aβ）诱导的神经元活动亢进的恶性循环所驱动的。因此，通过抑制神经元活动亢进来打破这个恶性循环可能是阻止AD进展的合理方法。支持这一观点的是，我们最近发现，在一个快速发病的早期AD小鼠模型（5xFAD）中，通过基因和药理学方法限制兰尼碱受体2（RyR2）的开放时间可预防神经元活动亢进、记忆障碍、树突棘丢失和神经元细胞死亡。在此，我们评估了在一个相对较晚发生、进展缓慢的AD小鼠模型（3xTG-AD）中限制RyR2开放时间对AD相关缺陷的影响，该模型与人类AD更为相似（与5xFAD相比）。通过行为测试、长时程增强记录以及高尔基和尼氏染色，我们发现，显著缩短RyR2通道开放持续时间的RyR2-E4872Q突变可预防3xTG-AD小鼠的学习和记忆障碍、长时程增强缺陷、树突棘丢失和神经元细胞死亡。此外，用R-卡维地洛药理学缩短RyR2开放时间可挽救3xTG小鼠的这些AD相关缺陷。因此，限制RyR2开放时间可能提供一种有前景的、以神经元活动亢进为靶点的抗AD策略。
