Heterogenous microglial reactivity contrasts with stable vascular transcriptional programs in mouse models of Alzheimer’s, CADASIL, and Traumatic Brain Injury
- K. D. Bjørnholm
- H. Li
- F. Del Gaudio
- G. Mocci
- W. Shao
- E. Baldisseri
- S. B. Rao
- C. Lindblad
- A. Fletcher-Sandersjöö
- E. Vázquez-Liébanas
- R. Pietilä
- L. Muhl
- R. Jiang
- C. Kalantzi
- J. Cheung
- S. Jin
- M. Svensson
- S. A. J. Lesnik Oberstein
- S. Syvänen
- M. A. Mäe
- R. Torp
- U. Lendahl
- H. Karlström
- E. P. Thelin
- P. Nilsson
- M. Vanlandewijck
2026-07-16
The extent to which the cerebrovasculature is affected in various brain disorders is still not well understood. To address this, we established a transcriptomic repository of major vascular cell types and microglia to compare the global transcriptomic response in mouse models of three human brain disorders linked to neuroinflammation and associated vascular reactivity: Alzheimer’s disease (AD), traumatic brain injury (TBI), and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Single-cell analysis of >250,000 cells at different disease stages led to identification of two previously unknown vascular cell subtypes, expanded the endothelial zonation spectrum and allowed for a detailed analysis of the cellular and molecular responses. Surprisingly, most vascular cell types lacked major transcriptomic changes across the three conditions, while microglia exhibited significant, disease-specific transcriptional changes. Notably, microglial responses converged between late-stage TBI and AD, offering insights into the predisposition for neurodegeneration following TBI.