Cell Logistics Research Center, School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
Department of Neurosurgery, Chonnam National University Research Institute of Medical Science, Chonnam National University Hwasun Hospital and Medical School, Jeollanam-do 58128, Republic of Korea.
Brain Res. 2022 Aug 1;1788:147924. doi: 10.1016/j.brainres.2022.147924. Epub 2022 Apr 22.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia. Amyloid-β (Aβ) has long been considered a key cause of neurodegeneration in the AD brain. Although the mechanisms underlying Aβ-induced neurodegeneration are not fully understood, a number of recent studies have suggested that intracellular calcium overload mediates this process. In this study, we focused on the cellular function of phospholipase C-β1 (PLCB1), which regulates calcium signaling by mediating hydrolysis of phosphatidylinositol 4,5-bisphosphate through G-protein coupled receptor pathways. First, we confirmed that acetylcholine-induced calcium release from intracellular stores of SH-SY5Y cells was significantly increased with Aβ oligomer treatment. We further found that PLCB1 expression was upregulated in Aβ-treated cells, and PLCB1 overexpression in SH-SY5Y cells elicited the calcium overload observed in Aβ-treated cells. In addition, Aβ oligomer-induced calcium overload in SH-SY5Y cells was alleviated by knockdown of PLCB1, indicating that PLCB1 plays an essential role in the neurotoxic process initiated by Aβ. The elevation of PLCB1 expression was confirmed in the brain tissues from the 5× familial AD (5×FAD) model mice. These findings suggest that PLCB1 may represent a potential therapeutic target for protecting neuronal cells against excitotoxicity in AD progression.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，也是痴呆症的主要病因。淀粉样蛋白-β（Aβ）长期以来被认为是 AD 大脑中神经退行性变的关键原因。尽管 Aβ 诱导的神经退行性变的机制尚未完全阐明，但最近的许多研究表明，细胞内钙超载介导了这一过程。在这项研究中，我们专注于磷脂酶 C-β1（PLCB1）的细胞功能，它通过 G 蛋白偶联受体途径介导磷脂酰肌醇 4,5-二磷酸的水解来调节钙信号。首先，我们证实 Aβ 低聚物处理可显著增加 SH-SY5Y 细胞细胞内储存的乙酰胆碱诱导的钙释放。我们进一步发现 Aβ 处理的细胞中 PLCB1 表达上调，并且在 SH-SY5Y 细胞中过表达 PLCB1 可引起 Aβ 处理的细胞中观察到的钙超载。此外，通过 PLCB1 敲低可减轻 Aβ 低聚物诱导的 SH-SY5Y 细胞钙超载，表明 PLCB1 在 Aβ 引发的神经毒性过程中起关键作用。在 5×家族性 AD（5×FAD）模型小鼠的脑组织中证实了 PLCB1 表达的升高。这些发现表明，PLCB1 可能代表了一种有潜力的治疗靶点，可用于保护神经元细胞免受 AD 进展过程中的兴奋性毒性。
