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.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia, accounting for approximately 80% of all dementia cases (Anand et al, 2014)
Our results provide new insight into the effect of a systemic bacterial infection during neurodegeneration and provide an explanation why common bacterial infections, such as urinary tract infection or gum disease are risk factors for earlier onset and/or progression of cognitive decline in people with dementia
Summary
Alzheimer’s disease (AD) is the most common form of dementia, accounting for approximately 80% of all dementia cases (Anand et al, 2014). Serum levels of inflammatory cytokines are significantly increased in people with dementia compared to healthy controls (Stoeck et al, 2014; Dursun et al, 2015; Ott et al, 2018) and clinical studies show that low-grade systemic inflammation, for example following a bacterial or viral infection, can modify neuropathology and this is linked to a faster rate of cognitive decline (Holmes et al, 2003; Heneka et al, 2015; Ide et al, 2016; Rakic et al, 2018). These studies show that systemic microbial infections or bacterial sepsis can lead to enhanced amyloid load, neuroinflammation and cognitive impairment in transgenic models of AD, but the effect on a real live, low-grade bacterial infection in a prion model has not yet been studied
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