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Mitochondrial double-stranded RNA accumulation in brain aging and Alzheimer's disease

Rachel L Doser1,2, Thomas J LaRocca1,2

  • 1Department of Health and Exercise Science, Colorado State University, Fort Collins, CO, USA.

Biorxiv : the Preprint Server for Biology
|February 12, 2026
PubMed

Insights

Mitochondrial double-stranded RNA (mt-dsRNA) accumulates with aging and Alzheimer's disease, driving inflammation and neurodegeneration. This study identifies mt-dsRNA as a key factor in brain aging and AD pathogenesis.

Area of Science:

  • Neuroscience
  • Immunology
  • Cell Biology

Background:

  • Mitochondria and inflammation are closely linked in aging and Alzheimer's disease (AD).
  • Mitochondrial double-stranded RNA (mt-dsRNA) is a suspected trigger of inflammation.
  • Understanding mt-dsRNA's role is crucial for neurodegenerative disease research.

Purpose of the Study:

  • To investigate mt-dsRNA accumulation and its signaling pathways in aging and AD brains.
  • To correlate mt-dsRNA levels with cognitive decline and neuropathology.
  • To explore the link between mitochondrial RNA homeostasis and neurodegeneration.

Main Methods:

  • Analysis of human brain tissue and in vitro transcriptomic datasets.
  • Quantification of mitochondrial transcripts and dsRNA editing.
  • Assessment of dsRNA antiviral signaling proteins and RNA processing machinery.

Main Results:

  • mt-dsRNA accumulation increases after midlife and is further elevated in AD brains.
  • Increased mt-dsRNA correlates with cognitive impairment, disease severity, and AD risk genotypes.
  • Reduced mitochondrial RNA processing and increased antiviral signaling suggest mt-dsRNA-driven inflammation.

Conclusions:

  • Mitochondrial RNA homeostasis disruption, marked by mt-dsRNA accumulation, contributes to age- and AD-related neurodegeneration.
  • mt-dsRNA acts as a potential driver of chronic inflammation in the aging brain.
  • Targeting mt-dsRNA pathways may offer novel therapeutic strategies for AD.

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