Lipids in Human Brain Disease

人脑疾病中的脂质

• 批准号: 8148255
• 负责人: Stanley I. Rapoport
• 金额: $ 13.58万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8148255
• 关键词: Brain Diseases; Human; Lipids

LIPID COMPOSITION OF BIPOLAR DISORDER BRAIN. Docosahexaenoic (DHA) and arachidonic acid (AA) are critical to brain function and are concentrated in synaptic membrane phospholipids. Concentrations of each of them (measured as percent of total fatty acid) were reported reduced in bipolar disorder (BD) compared with control brain. However, in postmortem BD frontal cortex obtained under strict conditions, we did not find a significant concentration difference for either fatty acid from control, whether concentration was measured per brain gram wet weight or as percent of the total fatty acid concentration. The difference from the earlier report may be due to the different sources of brain tissue, or to the fact that we measured concentrations using added authentic standards. Since we reported altered AA metabolizing enzymes in the postmortem BD, we predict that measuring AA kinetics with our PET method would show brain abnormalities in BD patients (Igarashi et al., 2010). NEUROINFLAMMATION AND EXCITOTOXICITY IN BIPOLAR DISORDER. Bipolar disorder (BD) affects 1-2 % of the US population, and is a significant cause of morbidity and mortality. Cognitive decline, symptom worsening and brain atrophy indicate progression. We showed that this progression was related to neuroinflammation and excitotoxicity. In BD compared with control frontal cortex, we reported lower protein and mRNA levels of glutamatergic N-methyl-D-aspartate (NMDA) receptor subunits NR-1 and NR-3A, and higher levels of the inflammatory cytokine interleukin (IL)-1beta, the IL-1 receptor, myeloid differentiation factor 88, nuclear factor (NF)-kappaB subunits, and of markers of activated astrocytes and microglia (GFAP, iNOS and CD11b). These data confirm the pathological processes of excitotoxicity and neuroinflammation in BD. As similar changes occur in Alzheimer disease, comparable antiinflammatory-antiexcitotoxicity therapies might be considered for both disorders (Rao et al, 2010). UPREGULATED ARACHIDONIC ACID METABOLISM IN BIPOLAR DISORDER BRAIN Based on our report that mood stabilizers given to rats downregulated markers of brain arachidonic acid (AA), we hypothesized that these markers would be elevated in bipolar disorder (BD). We confirmed this hypothesis by showing that postmortem prefrontal cortex from BD compared with control subjects demonstrated increased expression of cytosolic phospholipase A2 (cPLA2) and cyclooxygenase (COX)-2, and of their respective AP-2 and NF-kB transcription factors. These changes are consistent with our hypothesis that mood stabilizers work in BD by dampening upregulated brain AA metabolism (Kim et al., 2009). APOPTOSIS AND SYNAPTIC LOSS IN BIPOLAR DISORDER BRAIN Bipolar disorder (BD) is associated with progressive brain atrophy and cognitive decline. We related these changes to evidence of cell death and synaptic loss in BD compared with control brain. We reported increased protein and mRNA levels of pro-apoptotic factors Bax, BAD, caspase-9 and caspase-3) and decreased levels of anti-apoptotic factors (BDNF and Bcl-2) and of synaptic markers (synaptophysin and drebrin) in BD compared with control postmortem prefrontal cortex. These changes are similar to changes in Alzheimer disease, suggesting a basis for common therapeutic approaches (Kim et al., 2010). DISTURBED G-PROTEIN MEDIATED NEUROTRANSMISSION IN BIPOLAR DISORDER Bipolar disorder (BD) symptoms are considered to arise from an imbalance of neurotransmission, and synaptic function. G-proteins couple certain neuroreceptors to signaling enzymes at the synapse, and are regulated by G-protein receptor kinases (GRKs). We reported decreased protein and mRNA levels of G-protein subunits β and γ and of GRK3 in postmortem frontal cortex from BD compared with control subjects. These results confirm synaptic dysregulation in BD. Our prior finding of positive effects of mood stabilizers on GRK3 thus may account in part for their therapeutic action in bipolar disorder (Rao et al., 2009).

双相情感障碍大脑的脂质组成。 Docosahexaenoic（DHA）和花生四烯酸（AA）对脑功能至关重要，并集中在突触膜磷脂中。与对照脑相比，据报道，它们中每一个的浓度（以总脂肪酸的百分比为单位）降低。但是，在严格条件下获得的验尸后BD额叶皮层中，我们没有发现任何一种脂肪酸都来自对照的浓度差，无论是每个脑革兰氏湿重还是总脂肪酸浓度的百分比。早期报告的差异可能是由于脑组织的不同来源，或者是由于我们使用添加的真实标准测量浓度的事实。由于我们报道了验尸BD中AA代谢酶的改变，因此我们预测，使用PET方法测量AA动力学将显示BD患者的脑异常（Igarashi等，2010）。 躁郁症中的神经炎症和兴奋性。 双相情感障碍（BD）影响美国人口的1-2％，这是发病率和死亡率的重要原因。认知能力下降，症状恶化和大脑萎缩表明进展。我们表明，这种进展与神经炎症和兴奋性毒性有关。在BD中，与对照额叶皮层相比，我们报告了谷氨酸甲基N-甲基-D-天冬氨酸（NMDA）受体亚基NR-1和NR-3A的蛋白质和mRNA水平较低，炎性细胞因子介体介菌（IL）-1BETA-1BETA，IL-1受体，MyEliation niviation nibiation Intubiation Isebiatiation isaliation Isebiation Isebers（NR-1），NR-1和NR-3A的较高水平（nr-1和NR-3A）。活化的星形胶质细胞和小胶质细胞（GFAP，INOS和CD11b）。这些数据证实了BD中兴奋性和神经炎症的病理过程。随着阿尔茨海默氏病的类似变化，可以考虑两种疾病的可比抗炎 - 抗炎毒性疗法（Rao等，2010）。 躁郁症大脑中的蛛网膜酸代谢上调 根据我们的报告，赋予大鼠的情绪稳定剂下调脑蛛网膜酸（AA）的标记，我们假设这些标记将在双相情感障碍（BD）中升高。我们通过表明BD的前额叶前皮层与对照组相比证明了这一假设，表明胞质磷脂酶A2（CPLA2）（CPLA2）和环氧酶（COX）-2及其各自的AP-2和NF-KB转录因子的表达增加。这些变化与我们的假设一致，即情绪稳定器通过抑制上调大脑AA代谢而在BD中起作用（Kim等，2009）。 双相情感障碍大脑的凋亡和突触丧失 躁郁症（BD）与进行性脑萎缩和认知能力下降有关。我们将这些变化与与对照脑相比，BD的细胞死亡和突触丧失的证据相关。 我们报道了促凋亡因子的蛋白质和mRNA水平BAX，BAD，CASPASE-9和CASPASE-3），与对照后frontem frontal frontal frontal frontal Cortex相比，BD的抗凋亡因子（BDNF和BCL-2）以及突触标记（BDNF和BCL-2）的水平降低。这些变化类似于阿尔茨海默氏病的变化，这表明了常见治疗方法的基础（Kim等，2010）。 G蛋白介导的双相情感障碍神经传递 双相情感障碍（BD）症状被认为是由于神经传递和突触功能的失衡而引起的。 G蛋白将某些神经感受器耦合到突触处的信号酶，并由G蛋白受体激酶（GRKS）调节。我们报告说，与对照组相比，我们报道了BD的蛋白质亚基β和γ和GRK3的蛋白质和mRNA水平降低。这些结果证实了BD的突触失调。因此，我们先前发现情绪稳定器对GRK3的积极影响可能部分解释了其在双相情感障碍中的治疗作用（Rao等，2009）。