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Published on: March 16, 2016
Cytomegalovirus-induced T cell responses accelerate Alzheimer's disease progression in mice
Morgan Marsden1,2, James E McLaren1,2, Ryan J Bevan3
1Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
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.
Insights
Systemic cytomegalovirus (CMV) infection in mice accelerates Alzheimer's disease (AD) pathology and cognitive decline. Antiviral treatment and T cell depletion reversed these effects, linking chronic viral infections to AD development.
Area of Science:
- Neuroscience
- Immunology
- Infectious Diseases
Background:
- Alzheimer's disease (AD) is a neurodegenerative disorder with complex etiology.
- Infections, particularly herpesviruses like cytomegalovirus (CMV), are increasingly implicated in AD pathogenesis.
Purpose of the Study:
- To investigate the mechanistic link between systemic viral infection and Alzheimer's disease progression.
- To determine the role of murine CMV (MCMV) infection in accelerating AD-like pathology in a mouse model.
Main Methods:
- Utilized transgenic 3xTg-AD mice to model Alzheimer's disease.
- Induced systemic infection with murine cytomegalovirus (MCMV).
- Analyzed cognitive function, tauopathy, synaptic loss, and immune cell infiltration in the brain.
Main Results:
- MCMV infection significantly accelerated cognitive decline, tauopathy, and hippocampal synaptic loss in 3xTg-AD mice.
- Accelerated disease was associated with brain infiltration of MCMV-specific CD8+ T cells.
- T cell depletion or antiviral therapy (valganciclovir) reversed cognitive deficits and reduced brain inflammation.
Conclusions:
- Systemic MCMV infection exacerbates Alzheimer's disease pathology and cognitive impairment.
- Virus-specific CD8+ T cells play a critical role in mediating infection-induced neuroinflammation and AD progression.
- Targeting viral infections may offer a therapeutic strategy for Alzheimer's disease.
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