# Impact of the Human Herpesvirus 6A (HHV6A) latency gene U94A on Alzheimer disease pathology

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2021 · $711,613

## Abstract

Abstract:
Alzheimer’s Disease (AD) is thought to be caused by a combination of multiple genetic and environmental
factors, and the role of infectious agents has been debated for decades. A recent multi-omic, epidemiological
study of large Alzheimer patient cohorts revealed a specific and significant association of human herpesvirus
6A (HHV6A) with AD. However, these studies could not resolve which HHV6A specific genes were involved or
how HHV6A might affect cells of the central nervous system (CNS) to exacerbate AD. As HHV6A is mainly
present in the brain in its latent form, we asked the question of whether the major latency associated gene
U94A, affects host cells functions that are relevant to Alzheimer disease pathology.
Using a human cell system, we found that U94A expression impairs the migration and maturation of human
glial progenitor cells (OPCs) and leads to synapse loss in human neurons. Preliminary transcriptomic and
proteomic analysis of U94A infected cells showed dysregulation of genes involved in cytoskeletal functions and
synaptic maturation. In addition, we found that expression of U94A increases accumulation of Aβ and
phosphorylation of Tau in cells co-expressing a familial Alzheimer disease (FAD)-linked, mutant APPswe
variant. These phenotypes are particularly relevant for the early stages of Alzheimer disease, as mounting
evidence suggests that synapse and neurite loss, associated with diffuse demyelination precede cognitive
impairment. Based on our published and preliminary data, we propose that the latency gene U94A represents
a disease-modifying factor that renders neural cells vulnerable to Alzheimer disease associated risk factors,
and exacerbates Alzheimer’s pathology in vitro and in vivo. We propose three Aims in which we test the
hypotheses that (i) U94A expression exacerbates Aβ accumulation in iPSC derived neural cells from familial
Alzheimer disease (FAD) patients and will exacerbate neuronal and glial cell impairments, (ii) that U94A
expression in the context of FAD mutations in mice will exacerbate cellular pathologies in vivo and (iii) that the
cellular impairments caused by U94A are sufficient to exacerbate cognitive deficits in familial Alzheimer’s
mouse models. This work will provide insight into the potential role of infectious agents in Alzheimer’s
pathology and will establish that HHV6A viral latency is not merely a benign state of viral infection, but an
important disease modifying factor.

## Key facts

- **NIH application ID:** 10380348
- **Project number:** 1R01AG075978-01
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** MARGOT MAYER-PROSCHEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $711,613
- **Award type:** 1
- **Project period:** 2021-09-30 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10380348

## Citation

> US National Institutes of Health, RePORTER application 10380348, Impact of the Human Herpesvirus 6A (HHV6A) latency gene U94A on Alzheimer disease pathology (1R01AG075978-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10380348. Licensed CC0.

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