Serotonin modulated mitochondrial dysfunction in Depression Diabetes and Dementia (3Ds)

项目摘要 我们的研究旨在了解5-羟色胺调控的线粒体生物发生在糖尿病中的作用。 抑郁症和痴呆症(阿尔茨海默病，AD)。糖尿病和抑郁症是高血压的独立危险因素。 并加重痴呆症的病理和治疗反应。抑郁症共病受损 代谢功能，如高血糖、胰岛素抵抗、炎症和氧化应激，会导致 身体抑郁和认知障碍。5-羟色胺是一种重要的神经递质， 衰老和痴呆中的突触传递、可塑性、能量稳态。很长时间以来，人们都知道 脑干拥有独特的神经元，可以合成5-羟色胺并将其投射到整个中枢神经系统。 然而，5-羟色胺水平与线粒体生物发生、线粒体动力学、 痴呆症、糖尿病和抑郁症中的有丝分裂吞噬/自噬还不完全清楚。现已确定 中缝背侧5-羟色胺的合成是细胞内稳态和能量代谢的保护性和必需的。它 已经假设低5-羟色胺水平会导致线粒体生物发生缺陷，受损 抑郁症患者的线粒体动力学、线粒体功能障碍和有丝分裂/自噬缺陷， 糖尿病、痴呆症和选择性5-羟色胺再摄取抑制剂，如西酞普兰治疗逆转 线粒体生物发生缺陷和所有线粒体缺陷方面。我们把这项研究概念化了。 在专注于3DS聚焦海马区(APP，Tau，HT22细胞)转基因模型的啮齿动物中， 下丘脑(DbDb，mHypo细胞)和中缝(TPH2/Ko，RN46A-B14细胞)。因此，目前的研究 建议了解西酞普兰(SSRI)的病理机制和对缺陷的保护作用 线粒体生物发生，线粒体动力学受损，以及有丝分裂吞噬/自噬缺陷。结果是 将为5-羟色胺在抑郁症、糖尿病和 痴呆与线粒体生物发生、线粒体动力学、线粒体功能和 有丝分裂吞噬/自噬。这一结果还将提供西酞普兰对常见疾病的有益效果 5-羟色胺引起的线粒体动力学、线粒体功能和有丝分裂/自噬缺陷。

Project Summary Our research aims to understand the role of serotonin modulated mitochondrial biogenesis in diabetes, depression, and dementia (Alzheimer's disease, AD). Diabetes and depression are independent risk factors for dementia and worsen the dementia pathology and therapeutic response. Depression comorbidity impaired metabolic function such as hyperglycemia, insulin resistance, inflammation, and oxidative stress results in physical depression and cognitive impairment. Serotonin is an essential neurotransmitter that performs synaptic transmission, plasticity, energy homeostasis in aging and dementia. For a long time, it is known that the brainstem harbors unique neurons to synthesize and project serotonin to the entire central nervous system. However, molecular links between serotonin levels and mitochondrial biogenesis, mitochondrial dynamics, mitophagy/autophagy in dementia, diabetes, and depression are not entirely understood. It is established that serotonin synthesis in dorsal raphe is protective and essential for cell homeostasis and energy metabolism. It has been hypothesized that low serotonin levels induce defective mitochondrial biogenesis, impaired mitochondrial dynamics, mitochondrial dysfunction and defective mitophagy/autophagy in depression, diabetes, and dementia, and selective serotonin reuptake inhibitors, such as citalopram treatment reverses defective mitochondrial biogenesis and all mitochondrial defective aspects. We have conceptualized the study in rodents focusing on the transgenic models of 3Ds focusing hippocampus (APP, Tau, HT22 cells), hypothalamus (DbDb, mHypo cells), and raphe (TPH2/ko, RN46A-B14 cells). Therefore, the current study proposes to understand the pathologies and the protective effects of citalopram (SSRI) against defective mitochondrial biogenesis, impaired mitochondrial dynamics, and defective mitophagy/autophagy. The outcome of our proposed experiments will provide new insights into the role of serotonin in depression, diabetes, and dementia concerning mitochondrial biogenesis, mitochondrial dynamics, mitochondrial function, and mitophagy/autophagy. The outcome will also provide beneficial effects of citalopram against common serotonin-induced defects of mitochondrial dynamics, mitochondrial function, and mitophagy/autophagy.