Spatial transcriptomics of the aging mouse brain reveals origins of inflammation in the white matter
To systematically understand age-induced molecular changes, we performed spatial transcriptomics of young, middle-aged, and old mouse brains and identified seven transcriptionally distinct regions. All regions exhibited age-associated upregulation of inflammatory mRNAs and downregulation of mRNAs related to synaptic function. Notably, aging white matter fiber tracts showed the most prominent changes with pronounced effects in females. The inflammatory signatures indicated major ongoing events: microglia activation, astrogliosis, complement activation, and myeloid cell infiltration. Immunofluorescence and quantitative MRI analyses confirmed physical interaction of activated microglia with fiber tracts and concomitant reduction of myelin in old mice. In silico analyses identified potential transcription factors influencing these changes. Our study provides a resourceful dataset of spatially resolved transcriptomic features in the naturally aging murine brain encompassing three age groups and both sexes. The results link previous disjointed findings and provide a comprehensive overview of brain aging identifying fiber tracts as a focal point of inflammation.
Authors
- Na Yang (ORCID: https://orcid.org/0000-0002-3292-7156)
- Ross A. McDevitt (ORCID: https://orcid.org/0000-0003-3722-9047)
- Chang-Yi Cui
- James R. Occean (ORCID: https://orcid.org/0000-0002-6823-6381)
- Manolis Maragkakis (ORCID: https://orcid.org/0000-0002-3158-1763)
- Sadia Afrin (ORCID: https://orcid.org/0000-0001-5063-9900)
- Nishat Sarker (ORCID: https://orcid.org/0000-0002-6050-7239)
- Payel Sen (ORCID: https://orcid.org/0000-0003-2809-0901)
- Supriyo De (ORCID: https://orcid.org/0000-0002-2075-7655)
- M. Okan İrfanoğlu (ORCID: https://orcid.org/0000-0001-8351-1516)
- Nirad Banskota (ORCID: https://orcid.org/0009-0000-5511-8346)
- Shahroze Abbas
- Elin Lehrmann (ORCID: https://orcid.org/0000-0002-9869-9475)
- Monica Bodogai (ORCID: https://orcid.org/0000-0002-8174-9608)
- Arya Biragyn (ORCID: https://orcid.org/0000-0001-5276-6102)
- Peter R. Rapp (ORCID: https://orcid.org/0000-0002-0983-3944)
- Christopher T. Lee (ORCID: https://orcid.org/0000-0002-0670-2308)
- Dan Benjamini (ORCID: https://orcid.org/0000-0002-9558-7056)
- Lin Wang (ORCID: https://orcid.org/0000-0002-2148-1929)
- Changyou Shi
- Jinshui Fan (ORCID: https://orcid.org/0009-0001-9300-1920)
Institutions
- University of Maryland, Baltimore (US)
- National Institute of Biomedical Imaging and Bioengineering (US)
- Institute on Aging (US)
- National Institute on Aging (US)
- Stanford University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-04
- DOI
- https://doi.org/10.1038/s41467-025-58466-2
- Citations
- 18
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 15.16
Funders
- National Institutes of Health