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Basic Science and Pathogenesis.

Stella R Wroblewski1, Sara Morris1, Gabrielle Blahusiak1

  • 1Tulane University, New Orleans, LA, USA.

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Summary
This summary is machine-generated.

Peripheral inflammation alters microglia, impacting brain cells long-term. These changes persist even after inflammation clears, potentially affecting neurodegeneration.

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Area of Science:

  • Neuroscience
  • Immunology
  • Genomics

Background:

  • Peripheral inflammation is a known risk factor for neurodegeneration.
  • Microglia, the brain's immune cells, are hypothesized to be affected by peripheral inflammation.
  • Previous studies indicate microglial transcriptional changes occur rapidly and persist long-term after inflammation.

Purpose of the Study:

  • To investigate the hypothesis that peripheral inflammation triggers transcriptional changes in microglia.
  • To determine the impact of these microglial changes on Alzheimer's disease (AD) pathology, specifically amyloid-beta (Aβ) and tau.
  • To analyze the long-term effects of peripheral inflammation on microglial homeostasis and neuronal interactions.

Main Methods:

  • 3xTg-AD mice were subjected to a peripheral viral infection to induce systemic inflammation.
  • Brain hemispheres were analyzed at 7 days and 2 months post-infection using immunostaining, Multiome sequencing (scRNA-seq and ATAC-seq), and spatial transcriptomics.
  • Circulating cytokine levels were measured using ELISA.

Main Results:

  • Spatial transcriptomics identified 265 differentially expressed genes in microglia and three unique microglial profiles at 7 days post-infection.
  • Algorithmic cell sorting suggested increased engulfment of glutamatergic neurons and endothelial cells by microglia.
  • At 2 months, microglia exhibited a pro-inflammatory phenotype with downregulated synaptic function genes, correlating with increased Apoe and Psen1&2 expression.

Conclusions:

  • Viral-induced peripheral inflammation significantly alters microglia state and homeostasis in a 3xTg-AD model.
  • Microglial transcriptional profiles remain altered long after systemic inflammation has cleared.
  • Peripheral inflammatory events induce lasting changes in microglia, with ongoing exploration into their implications for neurodegeneration.