Mechanisms and therapeutic potential of vagus nerve stimulation in aging and Alzheimer’s disease

项目总结。 三分之一的老年人表现出某种形式的认知缺陷，65岁以上的人中有13% 阿尔茨海默病的临床诊断。即使在没有明显病理的情况下，与年龄相关的认知 功能障碍可能严重到扰乱日常生活的工具性活动，因此， 保持个人独立性的能力。在衰老和阿尔茨海默病中，海马体支持的助记功能 由前额叶皮质(PFC)支持的(HPC)和执行功能特别容易衰退。 随着年龄的增长，HPC和PFC都会经历分子和电生理变化，从而扰乱平衡 在兴奋性和抑制性(E/I)信号之间传递最佳认知所必需的信号。此外，异常的E/I 衰老中的信号增加了对AD神经病理的易感性。此外，随着年龄的增长， 外周炎症可以失调E/I信号，加重AD的病理，损害认知。一种理想 因此，对改善衰老认知结果的干预将：1)有利于认知的多个方面 以最小的副作用发挥作用，2)在整个衰老的大脑中重建E/I平衡，3)减弱 阿尔茨海默病的病理堆积可能会加剧认知功能障碍，以及4)很容易被跨物种翻译。 迷走神经电刺激(VNS)治疗癫痫已有30年的历史，安全有效 和抑郁症，已发表的初步数据表明，它对中枢神经系统E/I有积极影响 发信号。VNS还可以降低AD患者外周血中的促炎细胞因子和tau水平。 最重要的是，在动物和人类受试者中的数据显示，VNS增强了多种形式的PFC--和 HPC依赖的认知在衰老过程中受到损害。尽管有这些有希望的发现，但VNS并没有 被严格评估为年龄相关性认知下降的潜在治疗方法。这项提议的目的是 是为了确定慢性VNS是否减轻了衰老的有害神经生物学和炎症后果 改善老年受试者的认知功能。我们的理由是，这样的研究将为 使用迷走神经作为衰老过程中认知障碍的治疗。我们的主要假设是慢性VNS 将通过恢复E/I平衡，减少炎症，预防AD，从而有益于认知衰老 相关病理学。目标1将确定VNS是否使分子和电生理正常化 E/I失调的特征，并减少衰老中的外周炎症标志物。目标2将决定 VNS是否可以补救多种形式的与年龄相关的认知障碍。AIM 3将使用有针对性的AAV- 一种确定VNS是否对神经病理和认知功能下降相关的保护作用的方法 患有类似AD的tau病理。这些实验将具有重要意义，因为它们将有助于确定VNS的效用 作为治疗衰老和阿尔茨海默病认知功能减退的干预手段。

PROJECT SUMMARY. One in three older adults exhibits some form of cognitive deficit, with 13% of individuals over age 65 meeting the clinical diagnosis of Alzheimer's disease (AD). Even in the absence of overt pathology, age-related cognitive dysfunction can be sufficiently severe as to disrupt instrumental activities of daily living and, consequently, the ability to maintain personal independence. In aging and AD, mnemonic functions supported by the hippocampus (HPC) and executive functions supported by the prefrontal cortex (PFC) are particularly vulnerable to decline. Both HPC and PFC undergo molecular and electrophysiological alterations with age that perturb the balance between excitatory and inhibitory (E/I) signaling necessary for optimal cognition. In addition, aberrant E/I signaling in aging increases susceptibility to AD neuropathology. Moreover, age-associated increases in peripheral inflammation can dysregulate E/I signaling, exacerbate AD pathology, and impair cognition. An ideal intervention for improving cognitive outcomes in aging would thus: 1) benefit multiple aspects of cognitive function with minimal side effects, 2) act to re-establish E/I homeostasis across the aged brain, 3) attenuate the accumulation of AD pathology that can worsen cognitive dysfunction, and 4) be readily translated across species. Electrical vagus nerve stimulation (VNS) has been used safely and effectively for 30 years to treat epilepsy and depression, and published and preliminary data show that it positively influences central nervous system E/I signaling. VNS also reduces pro-inflammatory cytokines in the periphery, as well as tau levels in AD patients. Most importantly, data in both animal and human subjects show that VNS enhances multiple forms of PFC- and HPC-dependent cognition that are compromised in aging. Despite these promising findings, VNS has not been rigorously evaluated as a potential treatment for age-associated cognitive decline. The objective of this proposal is to determine if chronic VNS mitigates deleterious neurobiological and inflammatory consequences of aging and improves cognitive function in aged subjects. Our rationale is that such studies will provide a foundation for use of VNS as a treatment for cognitive impairments in aging. Our overarching hypothesis is that chronic VNS will benefit cognition in aging by restoring E/I homeostasis, reducing inflammation, and protecting against AD- associated pathology. Aim 1 will determine whether VNS normalizes molecular and electrophysiological signatures of E/I dysregulation and reduces peripheral markers of inflammation in aging. Aim 2 will determine whether VNS remediates multiple forms of age-associated cognitive impairment. Aim 3 will use a targeted AAV- based approach to determine whether VNS protects against neuropathology and cognitive decline associated with AD-like tau pathology. These experiments will be significant as they will help to determine the utility of VNS as an intervention for treating cognitive decline in aging and AD.