Background: Systemic infections can exacerbate cognitive decline in Alzheimer’s disease (AD), yet the underlying molecular mechanisms remain poorly understood. Given the central role of astrocytes in the pathophysiology of AD, we tested the hypothesis that systemic infection promotes a shift in astrocyte function toward a proinflammatory neurotoxic phenotype, thereby accelerating pathology and cognitive decline.

Methods: An enriched population of GFAP⁺ astrocytes were isolated from the temporal cortex by laser capture microdissection from AD cases who died with (n=6) or without systemic infection (n=6) and matched control cases who died with (n=6) or without systemic infection (n=6). The astrocyte gene expression profile was interrogated using microarray analysis to identify novel mechanisms potentially impacted by systemic infection. 

Results: The presence of AD pathology resulted in the significant differential expression of 3,978 transcripts by astrocytes, the majority of which were downregulated (3,273) (FC≥1.5, p value <0.05), and primarily associated with impaired synaptic signalling (p=3.3×10^-7).  In response to systemic infection 1,156 genes (742 upregulated, 414 downregulated) were significantly differentially expressed by astrocytes in AD. Key pathways impacted by systemic infection included oxidative phosphorylation (p=1.3×10^-4), reactive oxygen species (p=2.8×10^-5) and neurodegeneration (p=1.3×10^-4).

Conclusion: Overall, our findings suggest that in AD astrocytes negatively impact synaptic signalling, and are primed to adopt a neurotoxic phenotype in response to infection, providing a basis for future candidate studies based on specific pathways.