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Transcriptomic Evidence of 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, Colorado, USA.

Aging Cell
|July 10, 2026
PubMed

Insights

Mitochondrial double-stranded RNA (mt-dsRNA) accumulation increases with brain aging and Alzheimer's disease, driving inflammation and neurodegeneration. This suggests mitochondrial RNA homeostasis is crucial for brain health.

Area of Science:

  • Neuroscience
  • Mitochondrial Biology
  • Immunology

Background:

  • Mitochondria and inflammation are closely linked in aging and Alzheimer's disease (AD).
  • Mitochondrial double-stranded RNA (mt-dsRNA) is emerging as a potential trigger for inflammation.
  • Understanding mt-dsRNA's role in brain aging and AD is critical for developing new therapeutic strategies.

Purpose of the Study:

  • To investigate the accumulation of mt-dsRNA and its associated signaling pathways in aging and AD brains.
  • To correlate mt-dsRNA levels with cognitive decline, neuropathology, and genetic risk factors for AD.
  • To elucidate the role of mitochondrial RNA homeostasis in age-related neurodegeneration and AD pathogenesis.

Main Methods:

  • Analysis of human brain tissue and in vitro transcriptomic datasets.
  • Quantification of mitochondrial transcripts and dsRNA editing.
  • Assessment of gene expression patterns related to RNA processing, translation, and antiviral signaling.

Main Results:

  • mt-dsRNA signatures increased post-midlife, correlating with reduced mitochondrial RNA processing and translation machinery.
  • Increased expression of dsRNA antiviral signaling proteins suggests cytoplasmic mt-dsRNA-driven inflammation.
  • In AD brains, elevated mt-dsRNA correlated with cognitive impairment, disease severity, and AD risk genotypes.

Conclusions:

  • Mitochondrial RNA homeostasis is an unrecognized factor in age- and AD-related neurodegeneration.
  • mt-dsRNA emerges as a significant potential driver of chronic neuroinflammation.
  • Altered ubiquitin-dependent regulation of antiviral signaling may indicate heightened sensitivity to mt-dsRNA in AD.
Keywords:
Alzheimer's diseaseagingbraindouble‐stranded RNAinflammationmitochondrial RNA

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