BDNF signaling in VMH astrocytes mediating energy and glucose balance control

VMH 星形胶质细胞中的 BDNF 信号介导能量和葡萄糖平衡控制

基本信息

批准号：
10116732
负责人：
Maribel Rios
金额：
$ 40.86万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10116732
关键词：
APP-PS1 Administrative Supplement Adult Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Animals Astrocytes Body Weight Brain region Brain-Derived Neurotrophic Factor Cells Chronic Consumption Data Dementia Desire for food Diet Disease Progression Electrophysiology (science)Equilibrium Exhibits Foundations Functional disorder Funding Future Glucose Glutamate Transporter Glutamates High Fat Diet Hippocampus (Brain)Human Hyperphagia Hypothalamic structure Impaired cognition Individual Insulin Resistance Intake Investigation Kinetics Length Mediating Metabolic dysfunction Metabolic stress Metabolic syndrome Modeling Molecular Morphology Mus Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neuronal Dysfunction Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Obesity Pathologic Pilot Projects Predisposition Prefrontal Cortex Process Receptor Signaling Reporting Risk Factors Role Senile Plaques Series Signal Transduction Synapses Testing Weight maintenance regimen cognitive function energy balance extracellular feeding global health hyperphosphorylated tau knock-down mouse model neural circuit parent grant reuptake uptake

项目摘要

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.

项目概要阿尔茨海默病 (AD) 是一种进行性神经退行性疾病，也是最常见的痴呆症。它困扰着越来越多的人，带来了灾难性的后果。是含有病理形式的抗体的淀粉样斑块和含有过度磷酸化的神经原纤维缠结人类关联和动物研究表明肥胖和伴随的代谢综合征。代谢功能障碍的这些假定影响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，我们理解并值得进行研究。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此行政补充申请的家长补助金是否调查。通过腹内侧星形胶质细胞中截短形式的 TrkB 受体 (TrkB.T1) 进行 BDNF 信号传导下丘脑（VMH）是一种介导能量平衡和体重控制的机制。表明 VMH 星形胶质细胞中的 TrkB.T1 抑制星形胶质细胞谷氨酸转运蛋白 GLT-1 的表达，突触谷氨酸清除作用提高了厌食 VMH 神经元的兴奋性。此外，我们发现长期摄入高脂肪饮食会提高正常小鼠的食欲。 TrkB.T1 在海马和前额皮质 (PFC) 中的表达，这两个大脑区域涉及认知这些发现与 AD 相关，因为 TrkB.T1 水平升高和降低。我们在 AD 大脑中分别报道了 HFD 诱导的肥胖和 Ab 。积累协同增加皮质和海马星形胶质细胞中 TrkB.T1 的水平。部分，阻碍突触谷氨酸清除和随后的细胞外谷氨酸积累突触功能障碍、兴奋性毒性、神经变性以及最终的认知能力下降为了检验这个想法。提出了一系列研究，检查 HFD 摄入对星形胶质细胞中 TrkB.T1 和谷氨酸的影响 AD 小鼠模型海马和 PFC 的摄取动力学这些研究结果将有所帮助。作为未来研究肥胖与 AD 发病之间关系的基础。