Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease
Year: 2024
Type: article
Study design: Observational Study
Abstract: Astrocytes play a critical role in brain homeostasis and normal functions but their changes along the spatiotemporal progression of Alzheimer’s 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.
Source: Nature Neuroscience
Authors: Alberto Serrano-Pozo, Huan Li, Zhaozhi Li, Clara Muñoz-Castro, Methasit Jaisa-aad, Molly A. Healey, Lindsay A. Welikovitch, Rojashree Jayakumar, Annie G. Bryant, Ayush Noori, Theresa R. Connors, Miwei Hu, Karen Zhao, Fan Liao, Gen Lin, Timothy Pastika, Joseph Tamm, Aicha Abdourahman, Taekyung Kwon, Rachel E. Bennett, Maya E. Woodbury, Astrid Wachter, Robert V. Talanian, Knut Biber, Eric H. Karran, Bradley T. Hyman, Sudeshna Das
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $12,290
OpenAlex ID: W4404224839