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Microglial double stranded DNA accumulation induced by DNase II deficiency drives neuroinflammation and

Ling-Jie Li1,2, Shi-Yu Liang1,2, Xiao-Ying Sun1

  • 1State Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Haidian District, Beijing, 100190, China.

Journal of Neuroinflammation
|January 20, 2025
PubMed
Abstract

Insights

Microglial deoxyribonuclease 2 (DNase II) deficiency exacerbates Alzheimer's disease pathology by activating inflammatory pathways and promoting DNA accumulation. Lowering DNase II levels in microglia may offer a therapeutic target for neurodegenerative diseases.

Area of Science:

  • Neuroscience
  • Immunology
  • Genetics

Background:

  • Deoxyribonuclease 2 (DNase II) clears cytoplasmic double-stranded DNA (dsDNA), and its deficiency is linked to neurodegeneration.
  • Microglial DNase II's role in neuroinflammation and Alzheimer's disease (AD) remains unclear.
  • Previous work linked neuronal DNase II deficiency to tau pathology.

Purpose of the Study:

  • To investigate the role of microglial DNase II in Alzheimer's disease pathogenesis.
  • To explore the impact of microglial DNase II deficiency on neuroinflammation and AD-related pathologies.

Main Methods:

  • Assessed microglial DNase II levels in 3xTg-AD mice.
  • Evaluated cognitive function in DNase II deficient mice using behavioral tests.
  • Analyzed microglial morphology, cGAS-STING and IFN-I pathway activation, neuroinflammation, synapse loss, amyloid pathology, and tauopathy.

Main Results:

  • Microglial DNase II levels were reduced in 3xTg-AD mice.
  • DNase II deficiency in microglia activated cGAS-STING and IFN-I pathways, increasing neuroinflammation.
  • This deficiency led to synapse loss, elevated amyloid-beta and tau pathology, and cognitive decline.

Conclusions:

  • Microglial DNase II deficiency contributes to neuroinflammation and AD pathology through cytoplasmic dsDNA accumulation.
  • The findings suggest DNase II as a potential therapeutic target for neurodegenerative diseases like AD.
Keywords:
Alzheimer's disease (AD)DNase IIDouble stranded DNA (dsDNA)NeuroinflammationType I interferons pathwaycGAS-STING pathway

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