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

> **NIH NIH P01** · UNIVERSITY OF COLORADO DENVER · 2021 · $374,620

## Abstract

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.

## Key facts

- **NIH application ID:** 10289595
- **Project number:** 3P01AG032958-13S1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Maria Acena Nagel
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $374,620
- **Award type:** 3
- **Project period:** 2009-03-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10289595

## Citation

> US National Institutes of Health, RePORTER application 10289595, The role of VZV infection in hippocampal neurons to  Alzheimer's disease pathogenesis (3P01AG032958-13S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10289595. Licensed CC0.

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