BDNF signaling in VMH astrocytes mediating energy and glucose balance control

项目摘要 阿尔茨海默病(AD)是一种进行性神经退行性疾病，是痴呆症最常见的形式。 它影响着越来越多的人，带来了毁灭性的后果。阿尔茨海默病的主要病理特征 淀粉样斑块是否含有病理形式的抗体和含有过度磷酸化的神经原纤维缠结 陶先生。人类协会和动物研究表明，肥胖及其伴随的代谢综合征 是AD的危险因素。代谢功能障碍的这些假定效应背后的机制仍然很差。 考虑到肥胖是一个全球性的健康问题，我们理解并需要进行检查。我们之前的研究 脑源性神经营养因子(BDNF)在中枢神经回路控制能量中的关键作用 和葡萄糖平衡。此行政补充申请的家长补助金调查是否 BDNF通过TrkB受体(TrkB.T1)截短型在腹内侧区星形胶质细胞中的信号转导 下丘脑(VMH)是调节能量平衡和体重控制的机制之一。到目前为止的数据 提示TrkB.T1在VMH星形胶质细胞中抑制星形胶质细胞谷氨酸转运体GLT-1和GLT-1的表达 突触谷氨酸清除。这一效应提高了厌食性VMH神经元的兴奋性张力，并 抑制食欲。此外，我们还发现，正常小鼠长期摄入高脂肪食物会增加 TrkB.T1在参与认知的两个脑区--海马区和前额叶皮质的表达 在阿尔茨海默病中的作用和影响。这些发现与AD相关，因为TrkB.T1水平的升高和降低 和GLT-1分别在AD脑中被报道。我们假设高脂饮食引起的肥胖和抗体 在大脑皮层和海马星形胶质细胞中，TrkB.T1的积累协同增加了TrkB.T1的水平。TrkB.T1，用于其 部分，阻碍突触对谷氨酸的清除，从而导致细胞外谷氨酸的积累 突触功能障碍、兴奋毒性、神经退化，最终导致认知能力下降。为了测试这一想法，我们 建议进行一系列研究，考察摄入HFD对星形胶质细胞TrkB.T1和谷氨酸的影响 阿尔茨海默病小鼠模型海马区和前额叶皮质的摄取动力学。这些调查的结果将有助于 作为未来研究肥胖与阿尔茨海默病发病关系的基础。

Project Summary Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. It afflicts an evergrowing number of individuals with devastating consequences. Key features of AD pathology are amyloid plaques holding pathological forms of Ab and neurofibrillary tangles containing hyperphosphorylated Tau. Human association and animal studies suggest that obesity and the accompanying metabolic syndrome are risk factors for AD. The mechanisms underlying these putative effects of metabolic dysfunction remain poorly understood and warrant examination considering that obesity is a global health problem. Our previous studies identified a critical role for brain-derived neurotrophic factor (BDNF) in central neural circuits controlling energy and glucose balance. The parent grant for this administrative supplement application investigates whether BDNF signaling through the truncated form of the TrkB receptor (TrkB.T1) in astrocytes in the ventromedial hypothalamus (VMH) is one mechanism mediating energy balance and body weight control. The data so far indicate that TrkB.T1 in VMH astrocytes inhibits expression of the astrocytic glutamate transporter GLT-1 and synaptic glutamate clearance. This effect elevates the excitatory tone onto anorexigenic VMH neurons and suppresses appetite. Moreover, we found that chronic intake of a high fat diet in normal mice elevates expression of TrkB.T1 in hippocampus and prefrontal cortex (PFC), two brain regions involved in cognitive function and affected in AD. These findings are relevant to AD because elevated and reduced levels of TrkB.T1 and GLT-1, respectively, have been reported in AD brain. We hypothesize that HFD-induced obesity and Ab accumulation cooperate to increase levels of TrkB.T1 in cortical and hippocampal astrocytes. TrkB.T1, for its part, impedes synaptic glutamate clearance and the consequent accumulation of extracellular glutamate elicits synaptic dysfunction, exitotoxicity, neurodegeneration and ultimately, cognitive decline. To test this idea, we propose a series of studies examining the effects of HFD consumption on TrkB.T1 in astrocytes and on glutamate uptake kinetics in hippocampus and PFC of a mouse model of AD. Findings from these investigations will serve as a foundation for future studies informing the relationship between obesity and the onset of AD.