Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer's disease

Serrano-Pozo, A.; Li, Z.; Woodbury, M. E.; Munoz-Castro, C.; Wachter, A.; Jayakumar, R.; Bryant, A. G.; Noori, A.; Welikovitch, L. A.; Hu, M.; Liao, F.; Lin, G.; Pastika, T.; Tamm, J.; Abdourahman, A.; Kwon, T.; Bennett, R. E.; Talanian, R. V.; Biber, K.; Karran, E. H.; Hyman, B. T.; Das, S.

doi:10.1101/2022.12.03.518999

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bioRxiv · 10.1101/2022.12.03.518999

Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer's disease

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Abstract

Astrocytes play a critical role in brain homeostasis and normal functions but their changes along the spatiotemporal progression of Alzheimers disease (AD) neuropathology remain largely unknown. Here we performed single-nucleus RNA-sequencing on brain regions along the stereotypical progression of AD pathology from donors ranging the entire normal aging-AD continuum comprising 628,943 astrocyte nuclei from 32 donors across 5 brain regions. We discovered temporal gene-expression-trajectories with gene sets differentially activated at various disease stages. Surprisingly, a gene set enriched in proteostasis and energy metabolism, was upregulated in late-stage but unexpectedly returned to baseline levels in end-stage, suggesting exhaustion of response in "burnt-out" astrocytes. The spatial gene-expression-trajectories revealed that astrocytic genes of tripartite synapses are dysregulated in parallel to the stereotypical progression of tangle pathology across regions. We identified astrocyte heterogeneity across brain regions with a continuum from homeostatic to reactive cells through "intermediate" transitional states. These findings suggest complex astrocytic dysfunction in AD neurodegeneration.

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Serrano-Pozo, A., Li, Z., Woodbury, M. E., Munoz-Castro, C., Wachter, A., Jayakumar, R., Bryant, A. G., Noori, A., Welikovitch, L. A., Hu, M., Liao, F., Lin, G., Pastika, T., Tamm, J., Abdourahman, A., Kwon, T., Bennett, R. E., Talanian, R. V., Biber, K., Karran, E. H., Hyman, B. T., Das, S.. 2022-12-07. Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer's disease. https://doi.org/10.1101/2022.12.03.518999

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