Detailed mapping shows how astrocytes change throughout Alzheimer’s disease progression

Astrocytes are star-shaped glial cells of 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 from Massachusetts General Hospital, Massachusetts Alzheimer’s Disease Research Center, Harvard Medical School and Abbvie Inc. set out to fill this gap in the literature.

Their article, published in Natural neuroscienceprovides one of the most detailed accounts to date of how different astrocyte subgroups respond to AD in different brain regions and at different stages of the disease, providing valuable insights into cellular dynamics of the disease.

“Our recent paper grew out of a growing awareness that while neurons have traditionally been at the forefront of Alzheimer’s research, other crucial brain cells, like astrocytes, have remained under the spotlight. -studied,” Sudeshna Das, lead author of the paper, told Medical Xpress.

“Astrocytes play a critical role in maintaining brain health and function, but their involvement in AD has been relatively underexplored. Inspired by recent advances in omics technologies that have significantly improved our understanding of molecular pathways, We sought to further explore the role of ‘outsider astrocytes in AD’.

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

“We conducted a comprehensive study using mononuclear RNA sequencing data on more than 600,000 nuclei from five brain regions representing the stereotypical progression of Alzheimer’s disease pathology,” Das said.

“These were collected from 32 donors ranging from healthy controls to those with advanced Alzheimer’s disease neuropathological change (ADNC). Our dataset of astrocyte transcriptomic profiles is one of the largest to date .”

Using these experimental methods, Das and colleagues were able to unveil spatial and temporal changes affecting astrocytes throughout AD progression. They then validated their results by immunohistochemistry, which allows visualization of proteins in tissues, and by fluorescent in situ hybridization using RNAScope, a method that allows detection of RNA sequences in tissue samples.

“We identified diverse subpopulations of astrocytes showing distinct responses depending on brain region and disease stage,” Das said. “Homeostatic astrocytes, which maintain brain synaptic function, decreased in regions with advanced AD neuropathology, while disease-associated reactive astrocytes increased proportionately.”

Das and colleagues also identified new “intermediate” states of astrocytes, which appear to be transitions between homeostatic and reactive forms of astrocytes. These intermediate states appeared to vary considerably in different brain regions and at different stages of AD.

“The study also revealed novel astrocytic states: a subpopulation rich in trophic factors that declined during pathological stages, as well as an ‘exhausted’ subpopulation that initially responded to pathology but returned to basic levels to final stages,” Das said. “This new state suggests an exhausted response to 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, this may inspire further research focused on astrocytes in AD, potentially informing the development of new therapeutic interventions.

“Together with our colleagues at AbbVie Inc, we have also studied the progression of microglial, endothelial and neuronal cells in AD,” added Das. “Our next step will be to understand how these cells interact with others to drive the neurodegeneration of Alzheimer’s disease. To this end, we will use spatial transcriptomics to map the gene expression patterns of these cells in situ in brain tissue.”

By mapping the gene expression patterns of different cell types in brain tissue, Das and his colleagues could gain new insights into their spatial organization and their relationship to Alzheimer’s disease. In future research, they also hope to use cellular or animal models of AD to determine whether the molecular processes they identify could become therapeutic targets, helping to advance the treatment of AD.

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