Effects of Hyperglycemia on Neuronal Activity, Cerebral Metabolism, and Amyloid-beta Levels

高血糖对神经元活动、大脑代谢和淀粉样蛋白水平的影响

基本信息

批准号：
9905321
负责人：
Shannon L Macauley-Rambach
金额：
$ 11.45万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9905321
关键词：
APP-PS1 Abeta synthesis Acute Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology American Amyloid beta-Protein Animals Area Behavior Behavioral Bilateral Blood Glucose Brain Brain region Cerebrum Chronic Collaborations Coupled Coupling Data Dementia Deposition Diabetes Mellitus Diagnosis Genetic Genetic Models Glucose Glucose Clamp Goals Health Care Costs Heterogeneity Hippocampus (Brain)Human Hyperglycemia Image Individual Insulin Insulin Resistance Intercellular Fluid K-Series Research Career Programs Link Mediating Mentors Mentorship Metabolic Diseases Metabolism Methodology Microdialysis Mus Nerve Degeneration Neurons Non-Insulin-Dependent Diabetes Mellitus Optics Pathology Patients Physiology Potassium Preparation Process Production Research Research Personnel Risk Role Senile Plaques Signal Transduction Synapses Synaptic plasticity Testing Time Training Work abeta deposition aged aging brain amyloid precursor protein processing awake base beta amyloid pathology blood glucose regulation cognitive function dementia risk epidemiology study glucose metabolism human model human old age (65+)in vivo interest mild cognitive impairment mouse model neuroimaging neuronal excitability normal aging overexpression public health relevance response

项目摘要

DESCRIPTION (provided by applicant): The goal of this K01 Mentored Career Development Award is to facilitate the transition of the individual to the role of an independent investigator y providing training and mentorship in the areas of glucose metabolism, Alzheimer's disease (AD), and type-2-diabetes (T2DM). Under the mentorship of Dr. David Holtzman, and in collaboration with Drs. Joseph Culver, Tamara Hershey, and Colin Nichols, the candidate will investigate the role of hyperglycemia on neuronal activity and functional connectivity as a function of age and pathology. Additionally, the candidate will receive extensive didactic and methodological training in the areas of small animal neuroimaging, KATP channel physiology, and AD-related research to help accomplish the goals set forth in the research application. Recent studies suggest that individuals with diabetes or those with elevated blood glucose levels have an increased risk for developing dementia or dementia due to AD; however, the mechanisms linking aberrant glucose metabolism, T2DM, and AD remain poorly understood. Our preliminary data suggests that acute increases in blood glucose levels have the ability to modulate amyloid-β (Aβ) levels in the brain, providing one explanation for the link between T2DM and AD. Yet it is unclear how age or pathology impacts the relationship between blood glucose levels, brain function, and Aβ metabolism. Moreover, our work suggests cerebral glucose metabolism is coupled with cellular excitability, neuronal activity, and Aβ metabolism via ATP-sensitive, inward rectifying potassium (KATP) channels; however, investigating whether chronic activation of KATP channels and increased cellular excitability is responsible for increased Aβ deposition warrants further study. To test the hypothesis that hyperglycemia regulates Aβ levels by KATP channel modulation and that this relationship is altered as a function of age and pathology, we will examine the following Aims: 1) Investigate the effects of hyperglycemia on neuronal activity, synaptic plasticity, and functional connectivity metabolism in a healthy brain as a function of normal aging. 2) Determine the effects of hyperglycemia on neuronal activity, network connectivity, and Aβ metabolism as a function of AD pathology using a genetic model of human APP overexpression. 3) Through the loss of KATP channel activity, we will uncouple glucose sensitivity from hyperexcitability in a mouse model of human APP overexpression and determine their effects on Aβ metabolism and neuronal activity.

描述（由适用提供）：这一K01指导职业发展奖的目标是促进个人向独立研究者的过渡，从而在葡萄糖代谢，阿尔茨海默氏病（AD）和2型2-糖尿病（T2DM）中提供训练和心态。在戴维·霍尔茨曼（David Holtzman）博士的心态下，并与博士合作。候选人约瑟夫·卡尔弗（Joseph Culver），塔玛拉·赫尔希（Tamara Hershey）和科林·尼科尔斯（Colin Nichols）将研究高血糖对神经元活性和功能连接性的作用，这是年龄和病理的函数。此外，候选人将在小型动物神经影像，KATP渠道生理学和与广告相关的研究领域接受广泛的教学和方法学培训，以帮助实现研究应用程序中规定的目标。最近的研究表明，患有糖尿病或血糖水平升高的人患AD引起的痴呆或痴呆症的风险增加。但是，将异常的葡萄糖代谢，T2DM和AD联系起来的机制仍然很少理解。我们的初步数据表明，血糖水平的急性增加具有调节大脑中淀粉样蛋白β（Aβ）水平的能力，为T2DM与AD之间的联系提供了一种解释。然而，尚不清楚年龄或病理如何影响血糖水平，大脑功能和Aβ代谢之间的关系。此外，我们的工作表明脑葡萄糖代谢与细胞刺激性，神经元活性和Aβ代谢相结合 ATP敏感的内向整流钾（KATP）通道；但是，研究KATP通道的慢性激活和细胞兴奋的增加是否导致Aβ沉积的增加需要进一步研究。为了测试高血糖通过KATP通道调节调节Aβ水平的假设，并且这种关系因年龄和病理的函数而改变，我们将研究以下目的：1）研究高血糖对神经元活性，突触性可变性，功能性连通性在健康的大脑中的作用性代谢的作用。 2）使用人类APP过表达的遗传模型确定高血糖对神经元活性，网络连通性和Aβ代谢的影响。 3）通过失去KATP通道活性，我们将在人类应用程序过表达的小鼠模型中脱离葡萄糖灵敏度，并确定它们对Aβ代谢和神经元活性的影响。