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Systemic inflammation accelerates changes in microglial and synaptic markers in an experimental model of chronic neurodegeneration

Systemic inflammation accelerates changes in microglial and synaptic markers in an experimental model of chronic neurodegeneration
Systemic inflammation accelerates changes in microglial and synaptic markers in an experimental model of chronic neurodegeneration
Bacterial infections are a common cause of morbidity and mortality in the elderly, and particularly in individuals with a neurodegenerative disease. Experimental models of neurodegeneration have shown that LPS-induced systemic inflammation increases neuronal damage, a process thought to be mediated by activation of “primed” microglia. The effects of a real systemic bacterial infection on the innate immune cells in the brain and neuronal networks are less well described, and therefore, in this study we use the ME7 prion model to investigate the alterations in microglia activation and phenotype and synaptic markers in response to a low grade, live bacterial infection. Mice with or without a pre-existing ME7 prion-induced neurodegenerative disease were given a single systemic injection of live Salmonella typhimurium at early or mid-stage of disease progression. Immune activation markers CD11b and MHCII and pro-inflammatory cytokines were analyzed 4 weeks post-infection. Systemic infection with S. typhimurium resulted in an exaggerated inflammatory response when compared to ME7 prion mice treated with saline. These changes to inflammatory markers were most pronounced at mid-stage disease. Analysis of synaptic markers in ME7 prion mice revealed a significant reduction of genes that are associated with early response in synaptic plasticity, extracellular matrix structure and post-synaptic density, but no further reduction following systemic infection. In contrast, analysis of activity-related neuronal receptors involved in development of learning and memory, such as Grm1 and Grin2a, showed a significant decrease in response to systemic bacterial challenge. These changes were observed early in the disease progression and associated with reduced burrowing activity. The exaggerated innate immune activation and altered expression of genes linked to synaptic plasticity may contribute to the onset and/or progression of neurodegeneration.
bacterial infection, microglia, neurodegeneration, synapses, systemic inflammation
1662-4548
Chouhan, Joe K.
5abf11d8-b889-4257-a53d-771428dcac39
Püntener, Ursula
324ad9b4-b69b-449b-85a2-27c2868f4e3c
Teeling, Jessica
fcde1c8e-e5f8-4747-9f3a-6bdb5cd87d0a
Booth, Steven
c2026d9d-ed93-4b1b-bce5-6b3efc8b8ca5
Chouhan, Joe K.
5abf11d8-b889-4257-a53d-771428dcac39
Püntener, Ursula
324ad9b4-b69b-449b-85a2-27c2868f4e3c
Teeling, Jessica
fcde1c8e-e5f8-4747-9f3a-6bdb5cd87d0a
Booth, Steven
c2026d9d-ed93-4b1b-bce5-6b3efc8b8ca5

Chouhan, Joe K., Püntener, Ursula, Teeling, Jessica and Booth, Steven (2022) Systemic inflammation accelerates changes in microglial and synaptic markers in an experimental model of chronic neurodegeneration. Frontiers in Neuroscience, 15, [760721]. (doi:10.3389/fnins.2021.760721).

Record type: Article

Abstract

Bacterial infections are a common cause of morbidity and mortality in the elderly, and particularly in individuals with a neurodegenerative disease. Experimental models of neurodegeneration have shown that LPS-induced systemic inflammation increases neuronal damage, a process thought to be mediated by activation of “primed” microglia. The effects of a real systemic bacterial infection on the innate immune cells in the brain and neuronal networks are less well described, and therefore, in this study we use the ME7 prion model to investigate the alterations in microglia activation and phenotype and synaptic markers in response to a low grade, live bacterial infection. Mice with or without a pre-existing ME7 prion-induced neurodegenerative disease were given a single systemic injection of live Salmonella typhimurium at early or mid-stage of disease progression. Immune activation markers CD11b and MHCII and pro-inflammatory cytokines were analyzed 4 weeks post-infection. Systemic infection with S. typhimurium resulted in an exaggerated inflammatory response when compared to ME7 prion mice treated with saline. These changes to inflammatory markers were most pronounced at mid-stage disease. Analysis of synaptic markers in ME7 prion mice revealed a significant reduction of genes that are associated with early response in synaptic plasticity, extracellular matrix structure and post-synaptic density, but no further reduction following systemic infection. In contrast, analysis of activity-related neuronal receptors involved in development of learning and memory, such as Grm1 and Grin2a, showed a significant decrease in response to systemic bacterial challenge. These changes were observed early in the disease progression and associated with reduced burrowing activity. The exaggerated innate immune activation and altered expression of genes linked to synaptic plasticity may contribute to the onset and/or progression of neurodegeneration.

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Accepted/In Press date: 30 November 2021
Published date: 4 January 2022
Keywords: bacterial infection, microglia, neurodegeneration, synapses, systemic inflammation

Identifiers

Local EPrints ID: 454202
URI: http://eprints.soton.ac.uk/id/eprint/454202
ISSN: 1662-4548
PURE UUID: aea1a977-ed16-46c8-a572-da3390ac0212
ORCID for Jessica Teeling: ORCID iD orcid.org/0000-0003-4004-7391

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Date deposited: 02 Feb 2022 17:45
Last modified: 28 Apr 2022 01:54

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Contributors

Author: Joe K. Chouhan
Author: Ursula Püntener
Author: Jessica Teeling ORCID iD
Author: Steven Booth

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