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

Marsden, M.; McLaren, J. E.; Bevan, R. J.; Penn-Ripley, D.; Somerville, M.; Lauder, S. N.; Gallimore, A.; Price, D. A.; Miners, K. L.; Ladell, K.; Siebzehnrubl, F. A.; Hughes, T. R.; Humphreys, I. R.; Clement, M.

doi:10.1101/2025.03.28.645902

bioRxiv · 10.1101/2025.03.28.645902

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

Marsden, M.·McLaren, J. E.·Bevan, R. J.·Penn-Ripley, D.·Somerville, M.·Lauder, S. N.·Gallimore, A.·Price, D. A.·Miners, K. L.·Ladell, K.·Siebzehnrubl, F. A.·Hughes, T. R.·Humphreys, I. R.·Clement, M.

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Abstract

Infections have long been implicated as causative factors in Alzheimers 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 {beta}-herpesvirus murine cytomegalovirus (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 CD8+ T cells specific for MCMV. Moreover, T cell receptor analyses revealed that these responses were clonally diverse, suggesting that multiple viral antigens were targeted in the brain during chronic infection with MCMV. T cell depletion during virus chronicity rescued infection-induced cognitive decline. In addition, antiviral drug treatment reduced lymphocytic infiltrates in the brain and reversed cognitive decline, suggesting potential clinical utility. These data provide a mechanistic link between chronic viral infections and the development of AD.

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Marsden, M., McLaren, J. E., Bevan, R. J., Penn-Ripley, D., Somerville, M., Lauder, S. N., Gallimore, A., Price, D. A., Miners, K. L., Ladell, K., Siebzehnrubl, F. A., Hughes, T. R., Humphreys, I. R., Clement, M.. 2025-04-02. Cytomegalovirus-induced T cell responses accelerate Alzheimer's disease progression in mice. https://doi.org/10.1101/2025.03.28.645902

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