The role of VZV infection in hippocampal neurons to Alzheimer's disease pathogenesis

水痘带状疱疹病毒（VZV）在90%的人群中潜伏，并重新激活产生带状疱疹

Varicella zoster virus (VZV) is latent in >90% of the population and reactivates to produce herpes zoster, as well as stroke (VZV vasculopathy). Similar to Alzheimer’s disease (AD), VZV reactivation is a disease of the elderly; produces cerebral ischemia/hemorrhage and neuroinflammation; and can present as long-term cognitive impairment and dementia. Furthermore, multiple epidemiological studies show that zoster significantly increases dementia risk and that antiviral therapy reduces risk. Our preliminary studies support the biological plausibility of VZV accelerating AD because VZV-infected spinal astrocytes produce intracellular amylin, Aβ42, and amyloid; cerebrospinal fluid (CSF) from VZV vasculopathy patients contain significantly elevated amyloid levels that correspond to anti-VZV antibody titers; and supernatant and CSF from VZV- infected cells/individuals induce amyloid formation. RNA sequencing analysis of VZV-infected sensory neurons show significant enrichment of AD-associated pathways compared to mock-infected cells, including increased amyloid processing, disruption of insulin signaling, complement activation and neuronal injury. Additional preliminary studies show deposition of amylin along VZV-infected sensory neuron processes and synapses; this finding is significant because in AD mouse models, amyloidogenic peptides along neurites have been shown to activate complement and tag the neurite for microglial pruning. Taken together, we hypothesize that, in conjunction with host and other environmental factors, VZV reactivation in the elderly accelerates AD progression by contributing to established pathological processes in AD, specifically neuroinflammation, amyloid deposition, and complement-mediated aberrant synaptic pruning and dysfunction. To test this hypothesis, we will: (Aim 1) Determine if VZV-infected primary human hippocampal neurons exhibit similar pathological changes as those described in AD, including production of a proinflammatory and amyloidogenic environment; and (Aim 2) characterize the role of VZV-induced complement activation in neuronal degeneration/dysfunction. Our studies are significant because understanding how VZV contributes to AD pathogenesis will provide early targets for diagnosis and treatment (i.e. zoster vaccination or prophylactic antiviral therapy) that may potentially slow or even halt progression to clinical dementia and death.