Cytomegalovirus-induced T cell responses accelerate Alzheimer’s disease progression in mice

Marsden, Morgan, McLaren, James E. ORCID: https://orcid.org/0000-0002-7021-5934, Bevan, Ryan J. ORCID: https://orcid.org/0000-0002-2557-2887, Penn-Ripley, Daisy, Somerville, Michelle, Lauder, Sarah N., Jones, Manon H., Maros, Lila-Blythe, McGurk, Matthew R., Gallimore, Awen ORCID: https://orcid.org/0000-0001-6675-7004, Price, David A. ORCID: https://orcid.org/0000-0001-9416-2737, Miners, Kelly L., Ladell, Kristin ORCID: https://orcid.org/0000-0002-9856-2938, Siebzehnrubl, Florian A. ORCID: https://orcid.org/0000-0001-8411-8775, Hughes, Timothy R. ORCID: https://orcid.org/0000-0003-2348-3490, Humphreys, Ian R. ORCID: https://orcid.org/0000-0002-9512-5337 and Clement, Mathew ORCID: https://orcid.org/0000-0002-9280-5281 2026. Cytomegalovirus-induced T cell responses accelerate Alzheimer’s disease progression in mice. Brain , awag043. 10.1093/brain/awag043

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Abstract

Infections have long been implicated as causative factors in Alzheimer’s disease (AD). Multiple studies have further suggested a key role for herpesviruses, such as cytomegalovirus (CMV). Using transgenic 3xTg-AD mice, we demonstrate that systemic infection with the β-herpesvirus murine CMV (MCMV) accelerates the development of cognitive decline, tauopathy and synaptic loss in the hippocampus, all of which are key features of AD. Accelerated disease progression after infection was associated with substantial lymphocyte infiltration into the brain, dominated by MCMV-specific effector memory CD8+ T cells expressing CXCR3. T cell receptor analyses revealed that clonally diverse virus-specific CD8+ T cells were selectively recruited into the brain during the development of AD. T cell depletion or treatment with the antiviral drug valganciclovir during chronic infection reduced lymphocytic infiltrates in the brain and reversed cognitive decline. These data provide a mechanistic link between chronic viral infections and the development of AD.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Medicine Schools > Biosciences
Publisher:	Oxford University Press
ISSN:	0006-8950
Funders:	MRC, Wellcome Trust
Projects:	MR/S07709/1, MR/X00922X/1, MR/X018318/1, 100326/Z/12/Z, 207503/Z/17/Z
Date of First Compliant Deposit:	14 July 2026
Date of Acceptance:	5 January 2026
Last Modified:	21 Aug 2026 13:37
URI:	https://orca.cardiff.ac.uk/id/eprint/188210

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