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（由申请人提供）：近40%的外科手术是在65岁或以上的患者中进行的，认知并发症很常见。全身麻醉也有牵连，老年人担心麻醉可能会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，一些全身麻醉剂会造成长期记忆障碍，并促进大脑中类似阿尔茨海默病（AD）的生化变化。特别是，常用的挥发性麻醉剂异氟烷会迅速增加淀粉样蛋白β（Aβ），这是一种与阿尔茨海默病的神经发病机制密切相关的蛋白质，并导致持久的记忆障碍，而同样广泛使用的地氟烷则不会。此外，在基线时脑A β水平升高的AD转基因小鼠中，生化变化被夸大，这意味着预先存在的脑淀粉样蛋白可能是麻醉诱导的认知能力下降的脆弱性因素。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，其导致突触抑制和神经元网络活动的异常模式，其中寡聚体Abeta在该过程中起主要作用。然而，没有研究调查麻醉剂诱导的Abeta增加对神经突触和网络的影响。我们建议在这里这样做，使用异氟烷和地氟烷麻醉和Arc：：dVenus报告小鼠和Arc：dVenus/PS1 AD转基因小鼠分别作为“正常”和Abeta负荷脑的模型。Arc是一种立即早期基因，是树突棘动力学和经验依赖性可塑性的中央调节因子，Arc：dVenus小鼠在Arc启动子的控制下过表达不稳定的Venus（dVenus），从而允许通过荧光显微镜直接观察到棘和神经元中的经验诱发活性。我们假设异氟烷麻醉后A β的增加在健康与A β负荷的大脑中具有不同的后果。我们提出，异氟烷诱导的Abeta增加导致树突棘（目的1）和2的崩溃。当预先存在的淀粉样蛋白负荷高时，在海马神经回路中产生异常的经验诱发活动模式（目的2），而不是其他情况，并且地氟烷没有影响。这项研究在科学上具有重要意义，因为它将阐明麻醉诱导的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，以及大多数患有轻度认知障碍（MCI）或AD的老年人，在基线时淀粉样蛋白升高，这项工作可能对改善老年外科患者的麻醉护理和降低认知发病率具有巨大的临床意义。