HMN 2025: How Microglia gene activity shifts across Alzheimer’s stages, revealing possible therapy targets

Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder that causes progressive memory loss and a decline in mental (i.e., cognitive) abilities. Statistics suggest that between 500,000 and 900,000 people are diagnosed with this disease every year, while several hundreds of thousands experience dementia or other aging-related cognitive decline.

While there are some available treatments designed to delay cognitive decline in individuals with mild or moderate AD symptoms, a cure for the disease has not yet been identified. A better understanding of the neural, genetic, cellular and molecular processes that contribute to the disease’s progression, as well as to neurodegeneration in general, could thus be highly valuable, as it could inform the future development of alternative treatments.

Past neuroscience research has identified the key role of microglia in AD. These are specialized immune cells that monitor the environment in the brain, clearing out damaged cells, debris and pathogens. The dysregulation of these cells has been linked to neurodegeneration and to the progression of AD.

Researchers at Icahn School of Medicine at Mount Sinai recently carried out a study to further investigate the cellular and molecular processes that regulate the function of microglia as AD advances and its symptoms become more severe.

Their findings, published in Nature Neuroscience, suggest that the gene activity of these immune cells changes considerably across different stages and sub-types of AD, while also identifying possible targets for future genetic or immunological therapies.

“Microglia are resident immune cells of the brain and are implicated in the etiology of AD and other diseases,” wrote Roman Kosoy, John F. Fullard, and their colleagues in their paper. “Yet the cellular and molecular processes regulating their function throughout the course of the disease are poorly understood.

“We present a transcriptional analysis of primary microglia from 189 human postmortem brains, including 58 healthy aging individuals and 131 with a range of disease phenotypes, such as 63 patients representing the full clinical and pathological spectra of AD.”

Essentially, Kosoy, Fullard and their colleagues performed in-depth genetic analyses on brain tissues collected from 189 deceased individuals, 131 of which had been diagnosed with AD at some point prior to their death. The remaining 58 individuals had relatively healthy brains and had not reported any cognitive decline.

The team isolated primary microglia (i.e., the main immune cells) from the tissues and used a technique known as RNA sequencing to measure the expression of genes in these cells. In addition, they ran analyses to detect different RNA versions produced by the same gene as well as gene-gene relationships. Finally, they tried to determine whether specific gene expression patterns in the microglia were linked to the severity of AD, dementia scores and neuropathological lesions in the patients prior to their passing.

“We identified changes associated with multiple AD phenotypes, capturing the severity of dementia and neuropathological lesions,” wrote the authors. “Transcript-level analyses identified additional genes with heterogeneous isoform usage and AD phenotypes.

“We identified changes in gene–gene coordination in AD, dysregulation of coexpression modules and disease subtypes with distinct gene expression patterns. Taken together, these data further our understanding of the key role that microglia have in AD biology and nominate candidates for therapeutic intervention.”

Overall, the results of the analyses run by Kosoy, Fullard and their colleagues further emphasize the key role of microglia in neurodegeneration and in the progression of AD. Ultimately, the researchers were able to identify distinct molecular subtypes of AD, marked by specific gene variants as well as expression and coordination patterns.

In the future, their findings could contribute to the development of alternative therapies or personalized treatment strategies for AD, dementia and potentially other diseases associated with neurodegeneration.

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