Astrocytes are star-shaped glial cells in the central nervous system that support neuronal function, maintain the blood-brain barrier, and contribute to brain repair and homeostasis. The evolution of these cells throughout the progression of Alzheimer's disease (AD) is still poorly understood, particularly when compared to that of neurons and other cell types.

Researchers at Massachusetts General Hospital, the Massachusetts Alzheimer's Disease Research Center, Harvard Medical School and Abbvie Inc. set out to fill this gap in the literature.

Their paper, published in Nature Neuroscience, provides one of the most detailed accounts to date of how different astrocyte subclusters respond to AD across different brain regions and disease stages, providing valuable insights into the cellular dynamics of the disease.

"Our recent paper emerged from a growing realisation that while neurons have traditionally been at the forefront of AD research, other crucial brain cells, like astrocytes, have remained understudied," Sudeshna Das, senior author of the paper, told Medical Xpress.

"Astrocytes play a vital role in maintaining brain health and function, yet their involvement in AD has been relatively underexplored. Inspired by recent advancements in omics technologies that have significantly enhanced our understanding of molecular pathways, we sought to delve deeper into the role of 'underdog' astrocytes in AD."

The key objective of the recent study by Das and her colleagues was to understand the role of astrocytes in AD progression. To do this, they looked at transcriptomic changes of astrocytes in brain regions affected by AD at different stages of the disease.

"We conducted an extensive study using single-nucleus RNA sequencing data on 600,000+ nuclei from five brain regions representing the stereotypical progression of AD pathology," said Das.

"These were taken from 32 donors ranging from healthy controls to those with advanced AD neuropathologic change (ADNC). Our dataset of astrocyte transcriptomics profiles is one of the largest to date."

Using these experimental methods, Das and her colleagues were able to unveil both spatial and temporal changes affecting astrocytes throughout the progression of AD. They then validated their findings through immunohistochemistry, which allows visualisation of proteins in tissues, and fluorescent in situ hybridisation using RNAScope, a method that enables the detection of RNA sequences within tissue samples.

"We identified various astrocyte subpopulations exhibiting distinct responses based on brain region and disease stage," said Das. "Homeostatic astrocytes, which maintain brain synaptic function, declined in regions with advanced AD neuropathology whereas reactive, disease-associated astrocytes increased in proportion."

Das and her colleagues also identified new "intermediate" astrocyte states, which appear to be transitions between the homeostatic and reactive forms of astrocytes. These intermediate states appeared to vary greatly across different brain regions and at different stages of AD.

"The study also revealed new astrocytic states: a trophic factor-rich subpopulation that declined along pathology stages, as well as a 'burnt-out' subpopulation that initially responded to pathology but returned to baseline levels at end-stages," said Das. "This new state hints at an exhausted response with chronic exposure to neuropathology,"

The detailed mapping of astrocyte responses produced by this research team contributes to the understanding of AD progression. In the future, it could inspire further research focusing on astrocytes in AD, potentially informing the development of new therapeutic interventions.

"With our colleagues at AbbVie Inc, we also studied the progression of microglia, endothelial, and neuronal cells in AD," added Das. "Our next step will be to understand how these cells interact with others to drive AD neurodegeneration. Towards that end, we will utilise spatial transcriptomics to map the gene expression patterns of these cells in situ within the brain tissue."

By mapping the gene expression patterns of different cell types within brain tissue, Das and her colleagues could gain new insight into their spatial organisation and their relationship to AD. In future research, they also hope to use cellular or experimental models of AD to determine whether any molecular processes they identify could become therapeutic targets, helping to advance AD treatment.