Research Spotlight: Learning More About How Astrocytes Change as a Result of Alzheimer’s Disease

Sudeshna Das, PhD, an investigator in the Department of Neurology at Massachusetts General Hospital and an associate professor of Neurology at Harvard Medical School, is the senior author of a recent paper in Nature Neuroscience, Astrocyte Transcriptomic Changes Along the Spatiotemporal Progression of Alzheimer’s Disease.

Alzheimer’s disease (AD) is defined by the widespread accumulation of amyloid-β plaques and phospho-tau neurofibrillary tangles.

These neuropathological changes are accompanied by a dramatic loss of synapses and neurons, along with profound changes in the morphology and function of astrocytes, cells that play a key role in brain health.

The molecular underpinnings of these changes, known as reactive astrogliosis, are largely unknown.

A deeper understanding of astrocytes’ roles is essential for developing targeted therapies to manage or prevent AD.

In this study, we collaborated with AbbVie Inc. to learn more about how astrocytes respond to the progression of AD.

Using advanced single-nucleus RNA-sequencing techniques, we analyzed 628,000 astrocytes from five brain regions affected by AD in 32 donors, spanning from normal aging to severe AD.

We identified various astrocyte subpopulations exhibiting distinct responses based on location and disease stage.

Homeostatic astrocytes, which maintain brain synaptic function, declined in regions with advanced AD neuropathology whereas reactive, disease-associated, astrocytes increased in proportion. Additionally, we identified "intermediate" states of astrocytes that serve as transitions between homeostatic and reactive forms, and showed significant variation across the stages and regions of AD.

The study also revealed new astrocytic states: a trophic factor-rich subpopulation that declined along pathology stages, and a “burnt-out” subpopulation that initially responded to pathology but returned to baseline levels at end-stages, suggesting an exhausted response with chronic exposure to neuropathology.

Our findings are available at https://ad-progression-atlas.partners.org.

This detailed mapping of astrocyte responses enhances our understanding of their roles in AD and may help identify potential targets for therapeutic intervention in the future.

Paper Cited:

Serrano-Pozo, A., Li, H., Li, Z. et al. Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease. Nat Neurosci 27, 2384–2400 (2024). https://doi.org/10.1038/s41593-024-01791-4