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