Alzheimer’s disease (AD) is the leading cause of dementia for which there is no cure. Neuropathological hallmarks include accumulation of insoluble forms of amyloid-beta into plaques located extracellularly and within vessels, aggregation of the microtubule protein tau in intracellular neurofibrillary tangles, ischemia, and neuroinflammation, leading to neuronal dysfunction and cognitive decline. A critical barrier in treating AD is the years- to decades-long lag from disease onset to clinical diagnosis, when reversal of brain pathology may, at best, slow cognitive decline. Thus, it is essential to identify early pathological processes that we can target to slow or halt AD progression. Varicella zoster virus (VZV) is a likely contributor to AD pathogenesis because of shared clinicohistopathological features. Like AD, VZV reactivation: 1) is a disease of older adults; 2) manifests as cognitive impairment/dementia; 3) produces cerebral ischemia/hemorrhage and neuroinflammation; and 4) produces intracellular amyloid and an amyloidogenic extracellular environment in vivo and in vitro. In addition, epidemiological studies show VZV reactivation (herpes zoster) increases dementia risk and antivirals reduce risk. In a separate line of research, exosomes are emerging as important mediators of AD pathogenesis, potentially contributing to neuroinflammation and neurotoxicity. Given that VZV induces an amyloidogenic and proinflammatory environment in plasma and cerebrospinal fluid of zoster and VZV vasculopathy patients, respectively, in the absence of infectious virions, the role of virus-induced, non-infectious exosomes in creating this environment in the central nervous system (CNS) is of great interest because it would explain, in part, why viral nucleic acids and virions are not consistently detected in AD brains. Our preliminary data show that compared to exosomes from mock-infected human sensory neurons (HuSNs; the cell type from which VZV reactivates), exosomes from VZV-infected HuSNs contain a single viral protein (VZV immediate early 62), as well as differentially-expressed cell proteins enriched for pathways associated with AD and infectious/immunomodulatory diseases. Furthermore, we found that these exosomes can enter CNS cells and functionally alter cellular phenotypes. Taken together, we hypothesize that VZV reactivation from HuSNs releases pathogenic, non-infectious exosomes into the CNS, resulting in neuroinflammation and neuronal dysfunction, overall contributing to AD pathology and accelerating progression to clinical dementia. To test this hypothesis, we will determine if exosomes from VZV-infected HuSNs induce inflammation and alter the transcriptome of CNS cells (Aim 1) and determine if exosomes from VZV-infected HuSNs inoculated intranasally or intraventricularly into 5xFAD mice induce acceleration of AD pathology and neurophysiological changes (Aim 2). Understanding how exosomes produced during VZV infection contribute to established pa...