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

项目摘要。 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%的人 阿尔茨海默病（AD）的临床诊断。即使没有明显的病理，与年龄相关的认知 功能障碍可能严重到足以破坏日常生活的工具性活动，因此， 保持个人独立的能力。在衰老和AD中，由海马支持的记忆功能 (HPC)由前额叶皮层（PFC）支持的执行功能特别容易下降。 HPC和PFC都随着年龄的增长而发生分子和电生理学变化，从而扰乱了平衡 兴奋性和抑制性（E/I）信号之间的最佳认知所必需的。此外，异常的E/I 衰老中的信号传导增加了对AD神经病理学的易感性。此外，与年龄相关的增加 外周炎症可使E/I信号传导失调，加重AD病理，并损害认知。一个理想 因此，改善老龄化认知结果的干预措施将：1）有利于认知功能的多个方面， 功能与最小的副作用，2）采取行动，重新建立E/I稳态整个老龄化的大脑，3）减弱 AD病理学的积累，其可恶化认知功能障碍，和4）容易跨物种翻译。 迷走神经电刺激（VNS）已被安全有效地用于治疗癫痫30年 和抑郁症，已发表和初步数据表明，它积极影响中枢神经系统E/I 发信号。VNS还降低了AD患者外周中的促炎细胞因子以及tau水平。 最重要的是，动物和人类受试者的数据表明，VNS增强了多种形式的PFC- 依赖HPC的认知在衰老中受损。尽管有这些有希望的发现，VNS还没有 被严格评估为与年龄相关的认知能力下降的潜在治疗方法。本提案的目的 是确定慢性VNS是否减轻了衰老的有害神经生物学和炎症后果 并改善老年人的认知功能。我们的理由是，这些研究将提供一个基础， 使用VNS作为衰老中认知障碍的治疗。我们的总体假设是慢性迷走神经综合征 将通过恢复E/I稳态、减少炎症和预防AD而有益于衰老中的认知。 相关病理学目的1将确定VNS是否使分子和电生理正常化 E/I失调的特征，并减少衰老中的炎症外周标志物。目标2将决定 VNS是否能修复多种形式的年龄相关认知障碍。Aim 3将使用靶向AAV- 基于方法来确定VNS是否可以防止神经病理学和认知功能下降相关 AD样tau病理学这些实验将是有意义的，因为它们将有助于确定VNS的效用 作为治疗衰老和AD中认知能力下降的干预措施。

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.