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  • 1University of Exeter, Exeter, United Kingdom.

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Systemic infections worsen Alzheimer's disease (AD) neuroinflammation by altering gene expression and cellular trafficking, particularly impacting the blood-brain barrier. This study reveals molecular mechanisms linking infection, AD, and immune responses.

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Area of Science:

  • Neuroscience
  • Genomics
  • Immunology

Background:

  • Alzheimer's disease (AD) is characterized by neuroinflammation, which is exacerbated by systemic infections.
  • Systemic inflammation activates microglia and increases dementia risk, accelerating cognitive decline in AD patients.

Purpose of the Study:

  • To investigate the molecular mechanisms of the central nervous system response to systemic infections in Alzheimer's disease.
  • To analyze changes in gene and microRNA (miRNA) expression in response to infection in AD.

Main Methods:

  • RNA and miRNA sequencing of prefrontal cortex tissue from 216 individuals with varying AD and infection statuses.
  • Differential gene and miRNA expression analysis using two-way ANOVA.
  • Weighted Gene Co-expression Network Analysis (WGCNA) to identify AD- and infection-associated modules.
  • Cell-type enrichment analysis to localize gene expression in brain cell types.

Main Results:

  • A gene module associated with both infection and AD was identified, highlighting viral budding and MAPK signaling pathways.
  • RIC8A, a gene upregulated during infection in AD, was linked to altered cellular trafficking, including Golgi vesicle transport.
  • Enriched gene expression was observed in blood-brain barrier (BBB) components like endothelial cells, pericytes, and astrocytes.
  • Initial sequencing suggests potential miRNA involvement in immune and vesicle transport pathways.

Conclusions:

  • Systemic infections impact neuroinflammation in AD through immune pathways and BBB dysfunction.
  • Altered cellular trafficking, indicated by vesicle transport enrichment, may be a mechanism by which infections affect the AD brain.
  • Further research integrating RNA and miRNA data is needed to confirm miRNA's role in regulating target gene expression.