Effect of Physiological Changes in Neuronal Activity AB Levels in Vivo

体内神经元活性AB水平的生理变化的影响

• 批准号: 8140767
• 负责人: Adam William Bero
• 金额: $ 3.28万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8140767
• 关键词: Acute; Affect; Alzheimer' s Disease; American; Biological Models; Biological Neural Networks; Brain; Brain region; Cells; Cessation of life; Data; Dementia; Deposition; Environment; Epidemiologic Studies; Event; Exercise; Exposure to; Extracellular Fluid; Extracellular Space; Half-Life; Hippocampus (Brain); Hour; Impaired cognition; Incidence; Intercellular Fluid; Investigation; Laboratories; Lead; Life; Life Style; Maps; Measurable; Measures; Mediating; Memory Loss; Microdialysis; Modeling; Motivation; Motor Cortex; Mus; Neurons; Pathogenesis; Pathology; Peptides; Physical activity; Physiological; Play; Process; Proteins; Public Health; Research Proposals; Rodent; Role; Seizures; Senile Plaques; Somatosensory Cortex; Synapses; Synaptic plasticity; System; Techniques; Tetrodotoxin; Therapeutic Intervention; Transgenic Mice; Vibrissae; Western Blotting; abeta accumulation; amyloid precursor protein processing; barrel cortex; cost; effective therapy; environmental enrichment for laboratory animals; in vivo; insight; novel; public health relevance; research study

DESCRIPTION (provided by applicant): Alzheimer's Disease (AD) is the leading cause of late-onset dementia and is characterized by progressive cognitive decline and memory loss, ultimately leading to death. Over 5 million Americans are currently suffering from AD, and the total costs of AD and other dementias exceed $145 billion annually. Understanding the pathogenesis of AD in order to ultimately develop effective treatments is therefore paramount and is the motivation for this research proposal. Accumulation of the amyloid beta (AP) peptide into oligomeric forms and insoluble amyloid plaques appears to play a critical role in AD pathogenesis. Conversion of soluble Ab into these toxic species is concentration-dependent. Thus, mechanisms that regulate the amount of Ab in the brain may act as key determinants of whether A (3will aggregate into toxic forms. Data from our laboratory and others have demonstrated that synaptic activity regulates Ab levels within the extracellular space of the brain (interstitial fluid - ISF). However, how ISF Ab levels change as a result of physiological alterations in synaptic activity is not known. Therefore, the objective of this proposal is to determine the effect of physiological manipulations that alter synaptic activity on ISF Ab levels in vivo. I hypothesize that physiological changes in neuronal activity dynamically regulate the release of Ab into the extracellular space of the brain. In Specific Aim 1,1 will stimulate the whiskers of a live mouse in order to elicit an acute increase in neuronal activity within the barrel cortex. During the stimulation period, I will use electrophysiological recording simultaneously with in vivo microdialysis in barrel cortex to measure neuronal activity and ISF Ab levels and observe how levels change during whisker stimulation. In Specific Aim 2, I will determine the effect of voluntary exercise on ISF Ab levels and neuronal activity in hippocampus and primary motor cortex by performing in vivo microdialysis with concurrent electrophysiological recording in these brain regions during exercise. I will also examine the effect of exercise on APP processing by extracting brains after exercise and measuring protein levels of APP derivatives by Western blot. In Specific Aim 3,1 will determine the effects of environmental enrichment on ISF Ab levels and neuronal activity using in vivo microdialysis and electrophysiological recording in the hippocampus following enrichment. Finally, I will use microdialysis to determine if enrichment alters Ab clearance from the extracellular space of the brain. Public Health Relevance: The relevance of this proposal to public health is that elucidating the mechanisms that regulate Ab levels in the brain under normal physiological conditions may provide novel insights into AD pathogenesis and may ultimately provide new opportunities for therapeutic intervention.

描述（由申请人提供）：阿尔茨海默病（AD）是迟发性痴呆的主要原因，其特征是进行性认知下降和记忆丧失，最终导致死亡。目前有超过500万美国人患有AD，AD和其他痴呆症的总成本每年超过1450亿美元。因此，了解AD的发病机制以最终开发有效的治疗方法是至关重要的，也是本研究提案的动机。淀粉样蛋白β（AP）肽积聚成寡聚体形式和不溶性淀粉样蛋白斑块似乎在AD发病机制中起关键作用。可溶性抗体转化为这些有毒物质是浓度依赖性的。因此，调节大脑中Ab数量的机制可能是A β是否聚集成毒性形式的关键决定因素。来自我们实验室和其他实验室的数据表明，突触活动调节脑细胞外空间（间质液- ISF）内的Ab水平。然而，如何ISF抗体水平的变化作为突触活动的生理变化的结果是未知的。因此，本提案的目的是确定改变突触活性的生理操作对体内ISF Ab水平的影响。我推测，神经元活动的生理变化动态调节抗体释放到脑细胞外空间。在特定目标1中，1将刺激活小鼠的胡须，以引起桶皮质内神经元活动的急剧增加。在刺激期间，我将使用电生理记录同时在桶皮质中的体内微透析来测量神经元活性和ISF Ab水平，并观察在晶须刺激期间水平如何变化。在具体目标2中，我将通过在运动期间在这些脑区域进行体内微透析并同时进行电生理记录来确定自愿运动对海马和初级运动皮层中ISF Ab水平和神经元活性的影响。我还将通过提取运动后的大脑并通过Western blot测量APP衍生物的蛋白质水平来检查运动对APP加工的影响。在具体目标3，1中，将使用体内微透析和富集后海马中的电生理记录来确定环境富集对ISF Ab水平和神经元活性的影响。最后，我将使用微透析来确定富集是否改变Ab从脑细胞外间隙的清除。公共卫生相关性：这一提议与公共卫生的相关性在于，阐明在正常生理条件下调节脑中Ab水平的机制可能为AD发病机制提供新的见解，并可能最终为治疗干预提供新的机会。