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bioRxiv · 10.64898/2026.02.02.703345

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

Doser, R. L.·LaRocca, T. J.
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Abstract

Mitochondria and inflammation are tightly linked in aging and Alzheimers disease (AD), and recent evidence implicates mitochondrial double-stranded RNA (mt-dsRNA) as a potential trigger of inflammation. We examined mt-dsRNA accumulation and dsRNA signaling in brain aging and AD using human brain tissue and complementary in vitro transcriptomic datasets, quantifying mitochondrial transcripts and dsRNA editing. We found that mt-dsRNA accumulated after midlife and coincided with reduced expression of mitochondrial RNA processing and translation machinery, along with increased expression of dsRNA antiviral signaling proteins, consistent with cytoplasmic mt-dsRNA-driven inflammation. In AD brains, mt-dsRNA accumulation was further increased and correlated with cognitive impairment, neuropathological severity, and AD risk genotypes. Genes associated with these measures reflected altered ubiquitin-dependent regulation of antiviral signaling, potentially indicating altered sensitivity to mt-dsRNA. Together, these findings highlight mitochondrial RNA homeostasis as an unrecognized contributor to age- and AD-related neurodegeneration by identifying mt-dsRNA as a potential driver of chronic inflammation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/703345v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@81f384org.highwire.dtl.DTLVardef@19a8138org.highwire.dtl.DTLVardef@99b597org.highwire.dtl.DTLVardef@1610120_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Doser, R. L., LaRocca, T. J.. 2026-02-04. Mitochondrial double-stranded RNA accumulation in brain aging and Alzheimer's disease. https://doi.org/10.64898/2026.02.02.703345

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