4.8 Article

cGAS/STING and innate brain inflammation following acute high-fat feeding

Journal

FRONTIERS IN IMMUNOLOGY
Volume 13, Issue -, Pages -

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2022.1012594

Keywords

cGAS; STING; acute; innate inflammation; microglia; high fat diet

Categories

Funding

  1. NIH [U01AG057562, U24DK115255, R01DK130913, T32DK007245]
  2. Sinai Medical Staff Foundation Research Fund for Studying Diet and Brain Health
  3. Robert and Katherine Jacobs Environmental Health Initiative
  4. Robert E. Nederlander Sr. Program for Alzheimer's Research
  5. Andrea and Lawrence A. Wolfe Brain Health Initiative Fund
  6. A. Alfred Taubman Medical Research Institute
  7. NeuroNetwork for Emerging Therapies
  8. Edith Briskin/SKS Foundation NeuroNetwork Emerging Scholar Fund
  9. Michigan Alzheimer's Disease Research Center early career investigator mentorship program
  10. NIH/NIA - Michigan Alzheimer's Disease Research Center [P30AG072931]
  11. NIH/NIA - University of Michigan Alzheimer's Disease Center
  12. NIA [K99/R00, 1K99AG071667-01A1]

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Obesity, prediabetes, and diabetes are associated with neurodegenerative diseases, particularly Alzheimer's disease and Alzheimer's disease related dementias, through the activation of innate inflammatory signaling, potentially via the cGAS/STING pathway.
Obesity, prediabetes, and diabetes are growing in prevalence worldwide. These metabolic disorders are associated with neurodegenerative diseases, particularly Alzheimer's disease and Alzheimer's disease related dementias. Innate inflammatory signaling plays a critical role in this association, potentially via the early activation of the cGAS/STING pathway. To determine acute systemic metabolic and inflammatory responses and corresponding changes in the brain, we used a high fat diet fed obese mouse model of prediabetes and cognitive impairment. We observed acute systemic changes in metabolic and inflammatory responses, with impaired glucose tolerance, insulin resistance, and alterations in peripheral immune cell populations. Central inflammatory changes included microglial activation in a pro-inflammatory environment with cGAS/STING activation. Blocking gap junctions in neuron-microglial co-cultures significantly decreased cGAS/STING activation. Collectively these studies suggest a role for early activation of the innate immune system both peripherally and centrally with potential inflammatory crosstalk between neurons and glia.

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