Common Pathogen Exposure Alters Gene Expression in the Mouse Brain

Objectives: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder causing cognitive and behavioral impairment especially in industrialized societies. Systemic atherosclerosis may play a role in cognitive deterioration. There are increasing evidence that pathogenic bacteria are contributing to the development of AD. We wanted to investigate in a mouse model the effects of Aggregatibacter actinomycetemcomitans and Chlamydia pneumonie infections on the gene expression in the brain.

Methods: Atherosclerosis-susceptible ApoE deficient mice were repeatedly inoculated either with A. actinomycetemcomitans (group Aa), C. pneumonie (group Cp), A. actinomycetemcomitans and C. pneumonie (group Aa+Cp) or saline (control group). Each group comprised 10 mice, and they were sacrificed 23 weeks after the first inoculation. RNA from the brain tissue was isolated with RNeasy Mini Kit (Qiagen). Targeted RNA sequencing analysis including altogether 285 genes related with AD and other neurodegenerative conditions was performed following the customized Miseq targeted NGS workflow (Illumina). Correlations between expression levels of differentially expressed genes and metabolic parameters measured from mice were determined by SPSS.
Results: When compared to the control group, 6, 14, and 3 genes were upregulated and 8, 3 and 3 genes were downregulated in groups Aa, Aa+Cp, and Cp, respectively (Q < 0.05). The most affected genes have functions in immunity, apoptosis, cell signaling and GABAergic processes. The expression levels of these genes correlated with several metabolic markers reflecting lipid homeostasis, and related especially with the liver phospholipid and polyunsaturated fatty acid levels. The serum IgG-class antibody level against A. actinomycetemcomitans correlated with the number of transcripts in the groups Aa and Aa+Cp.

Conclusions: Repeated inoculation of studied pathogens caused changes in the expression of several genes associated with AD and other neurodegenerative conditions in the mouse brain tissue. These effects may be mediated via dysregulation of lipid homeostasis.