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

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。全身麻醉已经牵涉其中，老年人担心麻醉可能会导致永久性记忆问题甚至痴呆。临床研究尚无定论，但临床前研究表明，一些全麻药物会造成长时间的记忆障碍，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醚会迅速增加淀粉样蛋白β (a β)，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，而地氟醚也被广泛使用，两者都不会。此外，在阿尔茨海默病转基因小鼠中，在基线时大脑β水平升高的生化变化被夸大，这意味着预先存在的大脑淀粉样蛋白可能是麻醉诱导的认知能力下降的易感因素。越来越多的证据表明，阿尔茨海默病主要是一种进行性突触功能障碍和丧失的疾病，导致突触抑制和神经网络活动的异常模式，寡聚β在这一过程中起主要作用。然而，没有研究调查了麻醉诱导的β增加对神经突触和网络的影响。我们建议在这里这样做，使用异氟醚和地氟醚麻醉和Arc::dVenus报告小鼠和Arc:dVenus/PS1 AD转基因小鼠分别作为“正常”和abeta负荷的大脑模型。Arc是一种直接早期基因，是树突脊柱动力学和经验依赖可塑性的中心调节因子。Arc：在Arc启动子的控制下，dVenus小鼠过度表达不稳定的Venus (dVenus)，使脊髓和神经元的经验诱发活动可以通过荧光显微镜直接观察到。我们假设异氟醚麻醉后β的增加对健康和β负荷的大脑有不同的影响。我们提出，异氟醚诱导的β增加导致树突棘塌陷（目的1）和2。当预先存在的淀粉样蛋白负担高而不是其他情况时，在海马神经回路中产生异常的经历诱发活动模式（Aim 2），并且地氟醚没有作用。这项研究具有重要的科学意义，因为它将阐明麻醉诱导的β增加的功能后果。此外，由于三分之一的无认知症状的老年人，以及大多数轻度认知障碍（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麻醉护理和降低老年外科患者的认知发病率具有巨大的临床意义。

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.