Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Biochem Pharmacol. 2023 Jan;207:115374. doi: 10.1016/j.bcp.2022.115374. Epub 2022 Dec 8.
Clinical and preclinical interest in Type 2 diabetes (T2D)-associated cognitive dysfunction (TDACD) has grown in recent years. However, the precise mechanisms underlying TDACD need to be further elucidated. Ferroptosis was reportedly involved in neurodegenerative diseases and diabetes-related organ injuries; however, its role in TDACD remains elusive. In this study, mice fed with a high-fat-diet combined with streptozotocin (HFD-STZ) were used as a T2D model to assess the role of ferroptosis in cognitive dysfunction. We found that ferroptosis was mainly activated in hippocampal neurons but not in microglia or astrocytes. Accordingly, increased levels of transferrin receptor and decreased levels of ferritin, GPX4, and SLC7A11 were observed in hippocampal neurons. In addition, pre-treatment with liproxstatin-1, a ferroptosis inhibitor, attenuated iron accumulation and oxidative stress response, which resulted in improved cognitive function in the HFD-STZ group. Furthermore, we found that p-AMP-activated protein kinase (AMPK) was decreased in the HFD-STZ group. Pre-treatment with AMPK agonist increased the expression of AMPK and GPX4, but decreased lipocalin 2 (LCN2) in the hippocampus that resulted in improved spatial learning ability in the HFD-STZ group. Taken together, we found that activation of neuronal ferroptosis in the hippocampus contributed to cognitive impairment of HFD-STZ mice. Furthermore, AMPK activation may reduce hippocampal ferroptosis, and consequently improve cognitive performance in diabetic mice.
近年来，2 型糖尿病（T2D）相关认知功能障碍（TDACD）的临床和临床前研究兴趣日益浓厚。然而，TDACD 的确切机制仍需进一步阐明。铁死亡被报道与神经退行性疾病和糖尿病相关的器官损伤有关；然而，其在 TDACD 中的作用仍不清楚。在这项研究中，使用高脂肪饮食联合链脲佐菌素（HFD-STZ）喂养的小鼠作为 T2D 模型，评估铁死亡在认知功能障碍中的作用。我们发现铁死亡主要在海马神经元中激活，而不在小胶质细胞或星形胶质细胞中激活。相应地，在海马神经元中观察到转铁蛋白受体水平升高，铁蛋白、GPX4 和 SLC7A11 水平降低。此外，铁死亡抑制剂 liproxstatin-1 的预处理减轻了铁积累和氧化应激反应，导致 HFD-STZ 组认知功能改善。此外，我们发现 HFD-STZ 组 p-AMP 激活蛋白激酶（AMPK）减少。AMPK 激动剂预处理增加了 AMPK 和 GPX4 的表达，但降低了海马中的脂质运载蛋白 2（LCN2），导致 HFD-STZ 组空间学习能力提高。总之，我们发现海马神经元铁死亡的激活导致 HFD-STZ 小鼠认知障碍。此外，AMPK 激活可能减少海马铁死亡，从而改善糖尿病小鼠的认知表现。
