Department of Neurology, Heilongjiang Provincial Hospital, Harbin, People's Republic of China.
HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, People's Republic of China.
Clin Interv Aging. 2021 Jun 22;16:1185-1191. doi: 10.2147/CIA.S304827. eCollection 2021.
High glucose (HG)-induced activation of mTOR promotes tau phosphorylation and leads to diabetes-associated dementia. This study aimed to explore the role of metastasis associated in lung adenocarcinoma transcript 1 (MALAT1) in HG-induced neuronal cell injury.
Hippocampus cells were isolated from C57BL/6J mice. After 6 days of culture, the cells were incubated with 5.5 mM glucose in normal medium or 75 mM glucose for 4 days. Cells were transfected with miR-144 mimic, miR-144 inhibitor, siRNA for MALAT1 or corresponding controls. Gene expression was detected by PCR and Western blot analysis.
HG increased the levels of MALAT1 and p-tau in hippocampal cells. Knockdown of MALAT1 partially reversed the effects of HG on mTOR activity and p-tau protein levels. MALAT1 functioned as competing endogenous RNA (ceRNA) for miR-144, and pre-treatment with MALAT1 siRNA decreased mTOR activity and p-tau protein level in HG-treated hippocampal cells, which was significantly attenuated by miR-144 mimics. Moreover, miR-144 negatively regulated the expression of mTOR and knockdown of MALAT1 suppressed mTOR, while overexpression of mTOR abrogated protective effects of MALAT1 knockdown in HG-treated hippocampal cells.
MALAT1 knockdown prevented HG-induced mTOR activation and inhibited tau phosphorylation. MALAT1 may be a therapy target for diabetes associated dementia.
高葡萄糖（HG）诱导的 mTOR 激活促进 tau 磷酸化，导致与糖尿病相关的痴呆。本研究旨在探讨肺腺癌转移相关转录物 1（MALAT1）在 HG 诱导的神经元细胞损伤中的作用。
从小鼠海马中分离出海马细胞。培养 6 天后，将细胞在正常培养基中用 5.5 mM 葡萄糖或 75 mM 葡萄糖孵育 4 天。用 miR-144 模拟物、miR-144 抑制剂、MALAT1 siRNA 或相应对照物转染细胞。通过 PCR 和 Western blot 分析检测基因表达。
HG 增加了海马细胞中 MALAT1 和 p-tau 的水平。敲低 MALAT1 部分逆转了 HG 对 mTOR 活性和 p-tau 蛋白水平的影响。MALAT1 作为 miR-144 的竞争性内源性 RNA（ceRNA），用 MALAT1 siRNA 预处理可降低 HG 处理的海马细胞中 mTOR 活性和 p-tau 蛋白水平，而 miR-144 模拟物可显著减弱这种作用。此外，miR-144 负调控 mTOR 的表达，敲低 MALAT1 抑制 mTOR，而过表达 mTOR 则可消除 MALAT1 敲低在 HG 处理的海马细胞中对 mTOR 的保护作用。
MALAT1 敲低可防止 HG 诱导的 mTOR 激活并抑制 tau 磷酸化。MALAT1 可能是治疗与糖尿病相关的痴呆的靶点。
