Team gains insight into genetic and molecular mechanisms that predispose individuals to Alzheimer's disease

Mount Sinai researchers have gained an unprecedented understanding of the genetic and molecular mechanisms of human microglia (immune cells in the brain), which could shed light on how they contribute to the development of Alzheimer’s disease and Progress provides valuable insights (ads). The team’s findings were published in Nature Genetics.

Using fresh human brain tissue obtained by biopsy or autopsy from 150 donors, researchers identified 21 Candidate risk genes and highlight one, SPI1, as a potential key regulator of microglia and AD risk.

“Our study is the largest analysis of human fresh-tissue microglia to date that may make it easier for someone to Genetic risk factors for Alzheimer’s disease,” said senior author Panos Roussos, MD, professor of psychiatry, genetics and genomic sciences at the Icahn School of Medicine, and director of the Sinai Center for Neurogenomics of Disease. “By better understanding the molecular and genetic mechanisms involved in microglial function, we are able to better uncover the regulatory landscape that controls this function and contributes to AD. This knowledge, in turn, could pave the way for new therapeutic interventions for Diseases for which there is currently no effective treatment.”

Microglia are primarily responsible for the immune response in the brain and are responsible for The development and maintenance of neurons is also critical. While previous studies, including some at Mount Sinai, have established that microglia play a key role in the genetic risk and development of Alzheimer’s disease, little is known about the epigenetic mechanisms by which this occurs very little. Because microglia are difficult to isolate in the human brain, most previous studies have used animal or cell line-based models that do not reflect the true complexity of microglia function in the brain. Another challenge is linking AD genetic risk variants to specific molecular functions, as these risk factors are often found in noncoding parts of the genome (formerly known as “junk DNA”), which are more difficult to study.

The Mount Sinai team’s solution is to obtain fresh brain tissue from biopsy or autopsy, which may be made by four Brain Bio – Depository, three at Mount Sinai and one from Rush University Medical Center/Rush Alzheimer’s Disease Center. “Using a total of 150 samples from these sources, we were able to isolate high-quality microglia that provide unprecedented insights into genetic regulation by reflecting the full set of regulatory components of microglia in both healthy and neurodegenerative patients, ” explained Dr. Roussos.

The process – comparing epigenetic, genetic, Gene Expression and Genetic Information – Allows researchers to comprehensively describe how microglia function is genetically regulated in humans. As part of their statistical analysis, they extended the results of previous genome-wide association studies to link identified AD-susceptible genetic variants to specific DNA regulatory sequences and genes whose dysregulation is known to directly contribute to disease development. They further describe the cell-wide regulatory mechanism as a method to identify genetic regions involved in specific aspects of microglial activity.

From their research, the scientists discovered new knowledge about the SPI1 gene, which Is a major microglial transcription factor regulating other transcription factors and gene networks genetically associated with AD. The data the team is generating is also important for deciphering the molecular and genetic mysteries behind other neurodegenerative diseases in which microglia play a role, including Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis .

PhD. Roussos acknowledges that his team still has a lot of work to do to fully understand how the identified genes contribute to the development and progression of Alzheimer’s disease, and how to target them for new treatments. However, he is encouraged by the results of single-cell analyses in his microglia lab using highly sophisticated instruments that reveal unique interactions between different types of immune cells in and around the brain associated with neurodegenerative diseases effect. “We are seeing very exciting results with our single-cell data,” reports Dr. Roussos, “which brings us one step closer to understanding gene-drive variants and cell-specificity in genetic diseases such as Alzheimer’s. Interaction.”