Libin Cardiovascular Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
Hotchkiss Brain Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
Alzheimers Dement. 2022 Nov;18(11):2088-2098. doi: 10.1002/alz.12543. Epub 2022 Jan 5.
Neuronal hyperactivity is an early neuronal defect commonly observed in familial and sporadic Alzheimer's disease (AD), but the underlying mechanisms are unclear.
We employed a ryanodine receptor 2 (RyR2) mutant mouse model harboring the R4496C mutation that markedly increases the channel's open probability (Po) to determine the impact of increased RyR2 activity in neuronal function without AD gene mutations.
Genetically increasing RyR2 Po induced neuronal hyperactivity in vivo in anesthetized and awake mice. Increased RyR2 Po induced hyperactive behaviors, impaired learning and memory, defective dendritic spines, and neuronal cell death. Increased RyR2 Po exacerbated the onset of neuronal hyperexcitability and learning and memory impairments in 5xFAD mice.
Increased RyR2 Po exacerbates the onset of familial AD-associated neuronal dysfunction, and induces AD-like defects in the absence of AD-causing gene mutations, suggesting that RyR2-associated neuronal hyperactivity represents a common target for combating AD with or without AD gene mutations.
神经元过度活跃是家族性和散发性阿尔茨海默病（AD）中常见的早期神经元缺陷，但潜在机制尚不清楚。
我们使用了一种肌质网钙释放通道 2（RyR2）突变小鼠模型，该模型携带 R4496C 突变，显著增加了通道的开放概率（Po），以确定在没有 AD 基因突变的情况下增加 RyR2 活性对神经元功能的影响。
遗传增加 RyR2 Po 可在麻醉和清醒的小鼠体内诱导神经元过度活跃。增加 RyR2 Po 可诱导过度活跃的行为、损害学习和记忆、破坏树突棘和神经元细胞死亡。增加 RyR2 Po 可加重 5xFAD 小鼠神经元过度兴奋和学习记忆障碍的发生。
增加 RyR2 Po 可加重家族性 AD 相关神经元功能障碍的发生，并在没有 AD 致病基因突变的情况下诱导 AD 样缺陷，表明 RyR2 相关神经元过度活跃代表了一种共同的靶点，可用于对抗 AD，无论是否存在 AD 基因突变。
