Cytoplasmic DNA Sensing Links LINE-1 Expression to Neuronal Senescence in Alzheimer's Disease

Herdy, J. R.; Taylor, E. E.; Karbacher, L.; Borgogno, O.; Traxler, L.; Lagerwall, J.; Huynh, V. A.; Lefterova, Z. V.; Kang, A.; Tosat-Bitrian, C.; Kelsey, M. M. G.; Sedivy, J.; Sinha, S.; Gan, L.; Bennett, C. F.; Reid, D.; Mertens, J.; Gage, F. H.

doi:10.64898/2026.07.27.740588

bioRxiv · 10.64898/2026.07.27.740588

Cytoplasmic DNA Sensing Links LINE-1 Expression to Neuronal Senescence in Alzheimer's Disease

Herdy, J. R.·Taylor, E. E.·Karbacher, L.·Borgogno, O.·Traxler, L.·Lagerwall, J.·Huynh, V. A.·Lefterova, Z. V.·Kang, A.·Tosat-Bitrian, C.·Kelsey, M. M. G.·Sedivy, J.·Sinha, S.·Gan, L.·Bennett, C. F.·Reid, D.·Mertens, J.·Gage, F. H.

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Abstract

Cellular senescence contributes to neurodegeneration in Alzheimers disease (AD), yet brain-penetrant senotherapeutic strategies remain limited. Here, we identify long interspersed nuclear element 1 (LINE-1) retrotransposons as key regulators of neuronal senescence and the senescence-associated-secretory-phenotype (SASP) in AD. Using transdifferentiated induced neurons (iNs) that preserve donor-specific aging-associated molecular signatures, we show that pharmacological inhibition of LINE-1 with nucleoside reverse transcriptase inhibitors (nRTIs) or antisense oligonucleotides reduces p16 expression, suppresses SASP and interferon-stimulated gene programs, and attenuates paracrine induction of reactive astrogliosis. Spatial transcriptomic analysis of human AD brain tissue further supports that senescent neurons with high LINE-1 expression are localized to inflammatory niches in the brain. Although bulk analysis finds no significant differences in LINE-1 expression between AD and control neurons, long-read single-cell RNA sequencing of iNs identifies a subset of neurons with elevated LINE-1 activity which display transcriptional signatures of neurodegeneration, immune activation, and senescence are enriched in AD relative to controls. RNA velocity analysis indicates that LINE-1 activation precedes the induction of canonical senescence markers, supporting a causal rather than consequential role. Mechanistically, LINE-1-derived cytoplasmic DNA activates the cGAS-STING innate immune pathway in post-mitotic neurons, and inhibition of cGAS phenocopies the effects of LINE-1 suppression. Together, these findings establish a LINE-1/cGAS-STING axis as a driver of neuronal senescence in AD and highlight LINE-1 inhibition as a tractable senomorphic strategy for neurodegenerative disease.

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Herdy, J. R., Taylor, E. E., Karbacher, L., Borgogno, O., Traxler, L., Lagerwall, J., Huynh, V. A., Lefterova, Z. V., Kang, A., Tosat-Bitrian, C., Kelsey, M. M. G., Sedivy, J., Sinha, S., Gan, L., Bennett, C. F., Reid, D., Mertens, J., Gage, F. H.. 2026-07-28. Cytoplasmic DNA Sensing Links LINE-1 Expression to Neuronal Senescence in Alzheimer's Disease. https://doi.org/10.64898/2026.07.27.740588

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