BDNF signaling in VMH astrocytes mediating energy and glucose balance control

项目摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种进行性神经退行性疾病，也是最常见的痴呆形式。 它使越来越多的人深受其害，并带来毁灭性后果。AD病理学的主要特征 是淀粉样蛋白斑块持有病理形式的抗体和神经元缠结含有过度磷酸化 τ的人类协会和动物研究表明，肥胖和伴随的代谢综合征， 是AD的危险因素。代谢功能障碍的这些假定效应的潜在机制仍然很差 考虑到肥胖是一个全球性的健康问题，这是一个值得理解和研究的问题。我们以前的研究 确定了脑源性神经营养因子（BDNF）在控制能量的中枢神经回路中的关键作用 和葡萄糖平衡。此行政补助申请的父母补助金调查是否 脑腹内侧核星形胶质细胞中通过TrkB受体截短形式（TrkB.T1）的BDNF信号传导 下丘脑（VMH）是调节能量平衡和体重控制的机制之一。迄今为止的数据 表明VMH星形胶质细胞中TrkB.T1抑制星形胶质细胞谷氨酸转运蛋白GLT-1的表达， 突触谷氨酸清除率这种效应提高了对致凋亡VMH神经元的兴奋性， 抑制食欲此外，我们发现，正常小鼠长期摄入高脂肪饮食， TrkB. T1在海马和前额叶皮质（PFC）中的表达，这两个脑区参与认知功能， 在AD中的作用和影响。这些发现与AD相关，因为TrkB.T1水平升高和降低 和GLT-1分别在AD脑中有报道。我们假设HFD诱导的肥胖和Ab TrkB.T1的积累协同增加皮质和海马星形胶质细胞中的TrkB.T1水平。TrkB.T1，由于其 部分，阻碍突触谷氨酸清除和随之而来的积累细胞外谷氨酸释放 突触功能障碍、兴奋毒性、神经变性和最终的认知衰退。为了验证这个想法，我们 我提出了一系列研究，检查HFD消耗对星形胶质细胞中TrkB.T1和谷氨酸的影响。 AD小鼠模型海马和PFC中的摄取动力学。这些调查的结果将有助于 作为未来研究肥胖与AD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.