Neuronal and vascular genome-maintenance states organize opposing multicellular architectures in the aging brain
- 1Penn State University College of Medicine, Neuroscience and Experimental Therapeutics Department, Hershey, PA
Abstract
Genome maintenance is usually treated as cell-intrinsic, yet brain cells age within multicellular neighborhoods. Whether a cell's DNA damage response (DDR) state is systematically embedded in native tissue architecture is unknown. We used MERFISH to map curated repair programs across 604,252 cells in matched sections from 2-3 and 22-month-old mice. Regional DDR expression and coordination formed an age-dependent mosaic, accompanied by immune and oligodendroglial shifts. Independent metacell and distance-resolved analyses identified a consistent anchor-dependent organization. Low-DDR neurons occupied immune- and OPC-oligodendroglial-rich niches. In contrast, DDR-high vascular anchors were associated with vascular-cell enrichment and, in cortex and cerebral nuclei, OPC-oligodendroglial enrichment, whereas immune cells were enriched around DDR-low vascular anchors. Thus, genome-maintenance state was associated with distinct anchor-cell-specific spatial context depending on anchor-cell identity and its DDR transcriptional state. These opposing neuronal and vascular patterns define anchor-dependent genome-maintenance niches as a spatial feature of brain aging, with implications for regional vulnerability.
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BibTeX
@misc{koshboresh2026neuronal,
title = {{Neuronal and vascular genome-maintenance states organize opposing multicellular architectures in the aging brain}},
author = {A. Koshboresh and V. L. Roy and M. Abdelmageed and S. B. Manjila and D. Parmaksiz and Y. Kim and J. Gillis and A. Paul},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.07.749801},
url = {https://www.biorxiv.org/content/10.64898/2026.09.07.749801v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Neuronal and vascular genome-maintenance states organize opposing multicellular architectures in the aging brain
AU - A. Koshboresh
AU - V. L. Roy
AU - M. Abdelmageed
AU - S. B. Manjila
AU - D. Parmaksiz
AU - Y. Kim
AU - J. Gillis
AU - A. Paul
PY - 2026
DA - 2026/09/07
PB - bioRxiv
DO - 10.64898/2026.09.07.749801
UR - https://www.biorxiv.org/content/10.64898/2026.09.07.749801v1
AB - Genome maintenance is usually treated as cell-intrinsic, yet brain cells age within multicellular neighborhoods. Whether a cell's DNA damage response (DDR) state is systematically embedded in native tissue architecture is unknown. We used MERFISH to map curated repair programs across 604,252 cells in matched sections from 2-3 and 22-month-old mice. Regional DDR expression and coordination formed an age-dependent mosaic, accompanied by immune and oligodendroglial shifts. Independent metacell and distance-resolved analyses identified a consistent anchor-dependent organization. Low-DDR neurons occupied immune- and OPC-oligodendroglial-rich niches. In contrast, DDR-high vascular anchors were associated with vascular-cell enrichment and, in cortex and cerebral nuclei, OPC-oligodendroglial enrichment, whereas immune cells were enriched around DDR-low vascular anchors. Thus, genome-maintenance state was associated with distinct anchor-cell-specific spatial context depending on anchor-cell identity and its DDR transcriptional state. These opposing neuronal and vascular patterns define anchor-dependent genome-maintenance niches as a spatial feature of brain aging, with implications for regional vulnerability.
ER -