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（由申请人提供）：K01 指导职业发展奖的目标是促进个人过渡到独立研究者的角色，在葡萄糖代谢、阿尔茨海默氏病 (AD) 和在 David Holtzman 博士的指导下，候选人将与 Joseph Culver、Tamara Hershey 和 Colin Nichols 博士合作，研究 2 型糖尿病 (T2DM)。此外，候选人还将接受小动物神经影像学、KATP 通道生理学和 AD 相关研究领域的广泛教学和方法培训，以帮助实现目标。最近的研究表明，患有糖尿病或血糖水平升高的人患痴呆症或 AD 痴呆的风险增加；然而，异常的葡萄糖代谢、T2DM 和 AD 之间的联系机制仍知之甚少。。我们的初步数据表明，血糖水平的急剧升高能够调节大脑中的淀粉样蛋白 - β (Aβ) 水平，这为 T2DM 和 AD 之间的联系提供了一种解释，但尚不清楚年龄或病理如何影响两者之间的关系。此外，我们的工作表明，脑葡萄糖代谢通过细胞兴奋性、神经元活动和 Aβ 代谢而耦合。 ATP 敏感的内向整流钾 (KATP) 通道；然而，研究 KATP 通道的慢性激活和细胞兴奋性增加是否导致 Aβ 沉积增加值得进一步研究，以检验高血糖通过 KATP 通道调节调节 Aβ 水平的假设。这种关系随着年龄和病理学的变化而改变，我们将检查以下目标：1）研究高血糖对神经元活动、突触可塑性和健康大脑中的功能连接代谢作为正常衰老的函数 2) 使用人类 APP 过度表达的遗传模型确定高血糖对神经元活动、网络连接和 Aβ 代谢的影响作为 AD 病理学的函数。 KATP 通道活性丧失后，我们将在人类 APP 过度表达的小鼠模型中将葡萄糖敏感性与过度兴奋分开，并确定它们对 Aβ 代谢和神经元活动的影响。