Role of ABeta in neural synapse and circuit remodeling following general anesthes

Aβ 在全身麻醉后神经突触和回路重塑中的作用

• 批准号: 8778370
• 负责人: GREGORY CROSBY
• 金额: $ 26.54万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8778370
• 关键词: A Mouse; Age-Years; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Anesthesia procedures; Anesthetics; Area; Behavioral; Biochemical; Brain; Caring; Cerebrum; Clinical; Clinical Research; Cognitive; Delirium; Dementia; Dendritic Spines; Elderly; Enzyme-Linked Immunosorbent Assay; Fluorescence Microscopy; Functional disorder; General Anesthesia; General anesthetic drugs; Health; Hippocampus (Brain); Image; Immediate-Early Genes; Impaired cognition; Impairment; Isoflurane; Learning; Mediating; Memory; Memory impairment; Modeling; Morbidity - disease rate; Morphology; Mus; Neurobehavioral Manifestations; Neurons; Neuropathogenesis; Operative Surgical Procedures; Patients; Pattern; Play; Process; Progressive Disease; Proteins; Psyche structure; Reporter; Research; Research Personnel; Rodent; Role; Senile Plaques; Staining method; Stains; Synapses; Testing; Time; Transgenic Mice; Venus; Vertebral column; Work; adverse outcome; density; dentate gyrus; desflurane; experience; improved; inhibitor/antagonist; mild cognitive impairment; morris water maze; neural circuit; neuronal patterning; older patient; overexpression; preclinical study; promoter; relating to nervous system; secretase; synaptic depression

DESCRIPTION (provided by applicant): Nearly 40% of surgical procedures are performed on patients 65 years of age or older and cognitive complications are common. General anesthesia has been implicated and seniors worry that the anesthesia might cause permanent memory problems or even dementia. Clinical studies are inconclusive but preclinical studies show that some general anesthetic agents produce prolonged memory impairment and promote Alzheimer's disease (AD)-like biochemical changes in the brain. In particular, the commonly used volatile anesthetic isoflurane rapidly increases amyloid β (Aβ), a protein strongly implicated in the neuropathogenesis of Alzheimer's disease, and causes long-lasting memory impairment, whereas desflurane, also widely used, does neither. Further, the biochemical changes are exaggerated in AD transgenic mice that have elevated levels of cerebral Abeta at baseline, implying pre-existing cerebral amyloid may be a vulnerability factor for anesthetic-induced cognitive decline. Mounting evidence indicates AD is primarily a disease of progressive synaptic dysfunction and loss that results in both synaptic depression and aberrant patterns of neuronal network activity, with oligomeric Abeta playing a major role in the process. However, no studies have investigated the impact of an anesthetic- induced increase in Abeta on neural synapses and networks. We propose to do so here, using isoflurane and desflurane anesthesia and Arc::dVenus reporter mice and Arc:dVenus/PS1 AD transgenic mice as models, respectively, of the 'normal' and Abeta-burdened brain. Arc is an immediate early gene that is a central regulator of dendritic spine dynamics and experience-dependent plasticity and Arc:dVenus mice overexpress destabilized Venus (dVenus) under control of the Arc promoter, allowing experience-evoked activity in spines and neurons to be directly visualized by fluorescence microscopy. We hypothesize that an increase in Abeta after isoflurane anesthesia has different consequences in the healthy vs. Abeta-burdened brain. We propose that an isoflurane-induced increase in Abeta causes collapse of dendritic spines (Aim 1) and 2. Generates abnormal patterns of experienced-evoked activity in hippocampal neural circuits (Aim 2) when the pre-existing amyloid burden is high but not otherwise, and that desflurane has no effect. This research is significant scientifically because it will clarify the functional consequences of anesthetic-induced increases in Abeta. Furthermore, because 1 in 3 older adults without cognitive symptoms, and most of those with mild cognitive impairment (MCI) or AD, have elevated amyloid at baseline, this work could have vast clinical implications for improving anesthetic care and reducing cognitive morbidity in geriatric surgical patients.

描述（由适用提供）：将近40％的手术程序是对65岁或以上的患者进行的，并且认知并发症很常见。已经暗示了全身麻醉，老年人担心麻醉可能导致永久性记忆问题甚至痴呆症。临床研究尚无定论，但临床前研究表明，某些一般麻醉剂会导致长时间的记忆力障碍，并促进阿尔茨海默氏病（AD）类似大脑的生物化学变化。特别是，常用的挥发性麻醉性异氟烷会迅速增加淀粉样β（Aβ），淀粉样β（Aβ）强烈与阿尔茨海默氏病的神经性发作有关，造成长期持久记忆障碍，并且持续的记忆障碍，而desflurane（也广泛使用）也没有。此外，在基线时脑abeta水平升高的AD转基因小鼠中，生化变化被夸大了，这表明先前存在的脑淀粉样蛋白可能是麻醉诱导认知能力下降的脆弱性因子。越来越多的证据表明，AD主要是一种进行性突触功能障碍和丧失的疾病，导致突触抑郁症和神经元网络活动的异常模式，而低聚的ABETA在此过程中起着重要作用。但是，尚无研究研究Anisothetic诱导的Abeta对神经元突触和网络的影响。我们建议在这里这样做，使用异氟烷和desflurane麻醉和Arc :: Dvenus Reporter小鼠和Arc：dvenus/ps1 AD转基因小鼠作为模型，分别是“正常”和Abeta含有的大脑的模型。 ARC是一个直接的早期基因，是树突状脊柱动力学和经验依赖性可塑性和弧形的中心调节因子：Dvenus小鼠过表达在电弧启动子控制下不稳定的金星（Dvenus），从而使经验丰富的活性在棘突和神经元中被荧光显微镜直接化。我们假设异氟烷麻醉后ABETA的增加在健康与ABETA负担的大脑中会产生不同的后果。我们提出，异氟烷引起的Abeta升高会导致树突状棘的崩溃（AIM 1）和2。当预先存在的淀粉样蛋白负担很高，但没有效应时，在海马神经元回路中会产生异常的经验诱发活性模式（AIM 2）。这项研究在科学上是显着的，因为它将阐明麻醉引起的ABETA增加的功能后果。此外，由于三分之一没有认知症状的老年人，大多数患有轻度认知障碍（MCI）或AD的年轻人在基线时淀粉样蛋白升高，因此这项工作可能具有巨大的临床意义，可改善麻醉性护理，并降低色膜手术患者的认知性发病率。