玉米莨菪苷通过增加 PP2A 的活性来抑制tau 病小鼠模型中的 Tau 过度磷酸化和聚集。
Cornel Iridoid Glycoside Suppresses Tau Hyperphosphorylation and Aggregation in a Mouse Model of Tauopathy through Increasing Activity of PP2A.
机构信息
Department of Pharmacy, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing Engineering Research Center for Nervous System Drugs, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing 100053, China.
Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
出版信息
Curr Alzheimer Res. 2019;16(14):1316-1331. doi: 10.2174/1567205017666200103113158.
BACKGROUND
rTg4510 mice are transgenic mice expressing P301L mutant tau and have been developed as an animal model of tauopathy including Alzheimer's Disease (AD). Cornel Iridoid Glycoside (CIG) is an active ingredient extracted from Cornus officinalis, a traditional Chinese herb. The purpose of the present study was to investigate the effects of CIG on tau pathology and underlying mechanisms using rTg4510 mice.
METHODS
The cognitive functions were detected by Morris water maze and objective recognition tests. Western blotting and immunofluorescence were conducted to measure the levels of phosphorylated tau and related proteins. Serine/threonine phosphatase assay was applied to detect the activity of protein phosphatase 2A (PP2A).
RESULTS
Intragastric administration of CIG for 3 months improved learning and memory abilities, prevented neuronal and synapse loss, halted brain atrophy, elevated levels of synaptic proteins, protected cytoskeleton, reduced tau hyperphosphorylation and aggregation in the brain of rTg4510 mice. In the mechanism studies, CIG increased the activity of PP2A, elevated the methylation of PP2A catalytic C (PP2Ac) at leucine 309, decreased the phosphorylation of PP2Ac at tyrosine 307, and increased protein expression of leucine carboxyl methyltransferase 1 (LCMT-1), protein tyrosine phosphatase 1B (PTP1B), and protein phosphatase 2A phosphatase activator (PTPA) in the brain of rTg4510 mice.
CONCLUSION
CIG might have the potential to treat tauopathy such as AD via activating PP2A.
背景
rTg4510 小鼠是一种表达 P301L 突变 tau 的转基因小鼠，已被开发为包括阿尔茨海默病（AD）在内的 tau 病动物模型。Cornel 环烯醚萜苷（CIG）是从传统中药山茱萸中提取的一种活性成分。本研究旨在探讨 CIG 通过 rTg4510 小鼠对 tau 病理学的影响及其潜在机制。
方法
通过 Morris 水迷宫和客观识别测试检测认知功能。Western blot 和免疫荧光法测定磷酸化 tau 及相关蛋白水平。丝氨酸/苏氨酸磷酸酶测定法检测蛋白磷酸酶 2A（PP2A）的活性。
结果
CIG 灌胃 3 个月可改善学习记忆能力，防止神经元和突触丢失，阻止脑萎缩，提高突触蛋白水平，保护细胞骨架，减少 rTg4510 小鼠脑内 tau 过度磷酸化和聚集。在机制研究中，CIG 增加了 PP2A 的活性，增加了 PP2A 催化亚基（PP2Ac）在亮氨酸 309 位的甲基化，降低了 PP2Ac 在酪氨酸 307 位的磷酸化，并增加了脑内亮氨酸羧基甲基转移酶 1（LCMT-1）、蛋白酪氨酸磷酸酶 1B（PTP1B）和蛋白磷酸酶 2A 磷酸酶激活剂（PTPA）的蛋白表达。
结论
CIG 通过激活 PP2A 可能具有治疗 AD 等 tau 病的潜力。
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