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

迷走神经刺激在衰老和阿尔茨海默病中的机制和治疗潜力

• 批准号: 10209090
• 负责人: JENNIFER Lynn BIZON
• 金额: $ 171.58万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10209090
• 关键词: Acute; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease patient; Animals; Attenuated; Biochemical; Brain; Brain region; Chronic; Cognition; Cognitive; Cognitive deficits; Data; Dependovirus; Drug Targeting; Elderly; Electric Stimulation; Electrophysiology (science); Epilepsy; Equilibrium; Exhibits; Foundations; GABA Receptor; Glutamate Receptor; Health; Hippocampus (Brain); Homeostasis; Human; Impaired cognition; Individual; Inflammation; Inflammatory; Intervention; Intractable Epilepsy; Learning; Link; Mediating; Mental Depression; Molecular; Nature; Nerve Degeneration; Neuraxis; Neurobiology; Outcome; Pathology; Peripheral; Population; Predisposition; Prefrontal Cortex; Public Health; Publishing; Rattus; Regimen; Reporting; Research; Risk; Rodent; Signal Transduction; Signaling Protein; Structure; Synapses; Testing; Therapeutic; Translating; Work; age related; aged; aging brain; base; clinical Diagnosis; cognitive benefits; cognitive function; cognitive performance; cytokine; executive function; experimental study; glutamatergic signaling; human old age (65+); human subject; improved; inflammatory marker; instrumental activity of daily living; meetings; neuropathology; novel; pre-clinical; prevent; rapid growth; relating to nervous system; side effect; tau Proteins; tau aggregation; tau expression; treatment group; vagus nerve stimulation

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.

项目摘要。 三分之一的老年人表现出某种形式的认知缺陷，其中 13% 的 65 岁以上老年人患有某种形式的认知缺陷 阿尔茨海默病（AD）的临床诊断。即使没有明显的病理学，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， 保持个人独立的能力。在衰老和 AD 中，海马体支持的记忆功能 （HPC）和由前额皮质（PFC）支持的执行功能特别容易下降。 HPC 和 PFC 都会随着年龄的增长而发生分子和电生理变化，从而扰乱平衡 最佳认知所必需的兴奋性和抑制性 (E/I) 信号之间的关系。此外，异常的 E/I 衰老过程中的信号传导增加了 AD 神经病理学的易感性。此外，与年龄相关的增加 外周炎症会导致 E/I 信号失调、加剧 AD 病理并损害认知。一个理想 因此，改善衰老认知结果的干预措施将：1）有益于认知的多个方面 具有最小副作用的功能，2) 重建衰老大脑的 E/I 稳态，3) 减弱 AD 病理的积累会加剧认知功能障碍，4) 很容易在物种间转化。 迷走神经电刺激 (VNS) 已安全有效地用于治疗癫痫 30 年 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 还可以降低外周促炎细胞因子以及 AD 患者的 tau 水平。 最重要的是，动物和人类受试者的数据表明，VNS 可增强多种形式的 PFC- 和 依赖于 HPC 的认知会随着年龄的增长而受到损害。尽管有这些有希望的发现，但 VNS 尚未被 被严格评估为与年龄相关的认知衰退的潜在治疗方法。本提案的目的 目的是确定慢性 VNS 是否可以减轻衰老带来的有害神经生物学和炎症后果 并改善老年受试者的认知功能。我们的理由是，此类研究将为 使用 VNS 作为治疗衰老认知障碍的方法。我们的首要假设是慢性 VNS 通过恢复 E/I 稳态、减少炎症和预防 AD-，有利于衰老过程中的认知 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，并减少衰老过程中炎症的外周标志物。目标 2 将决定 VNS 是否可以修复多种形式的与年龄相关的认知障碍。目标 3 将使用有针对性的 AAV- 基于方法来确定 VNS 是否可以预防相关的神经病理学和认知能力下降 具有类似 AD 的 tau 蛋白病理学。这些实验非常重要，因为它们将有助于确定 VNS 的效用 作为治疗衰老和 AD 认知能力下降的干预措施。