Using fresh human brain tissue collected by biopsy or autopsy from 150 donors, the researchers identified 21 prospective risk genes, one of which they highlighted, SPI1, as a potential key regulator of microglia and AD risk.
“Our study is the largest analysis to date of human fresh tissue microglia, whose genetic Risk factors may predispose someone to Alzheimer’s disease. By better understanding the molecular and genetic mechanisms involved in microglial function, we can better unravel the regulatory picture that controls this function and leads to AD. This This knowledge, in turn, could pave the way for novel therapeutic interventions for diseases for which there is currently no effective treatment.”
In addition to being critical to the development and maintenance of neurons, microglia play an important role in the brain’s immune response. Although previous studies, including some from Mount Sinai, have shown that microglia are important for genetic risk and progression of Alzheimer’s disease, little is known about the epigenetic mechanisms underlying this condition.
Most of the earlier studies employed animal or cell line-based models that did not accurately represent the true complexity of microglial activity in the brain, which is difficult to isolate in the human brain. Because these risk variables frequently occur in noncoding regions of the genome (previously referred to as “junk DNA”), which are more challenging to analyze, it has been difficult to link genetic risk variants for AD to specific molecular functions.
The Mount Sinai team’s solution is to obtain fresh brain tissue from biopsies or autopsies through a collaboration between four brain biorepositories, three at Mount Sinai and one from Rush University Medical Center/Rush Alts Haymer’s Disease Center. “Using a total of 150 samples from these sources, we were able to isolate high-quality microglia, providing unprecedented insights into genetic regulation by reflecting the full set of regulatory components of microglia in healthy and neurodegenerative patients,” Roussos Dr. explained.
This process — comparing epigenetics, gene expression and genetic information from AD and healthy older patient samples — allowed the researchers to fully characterize how microglia function is genetically regulated in humans. As part of their statistical analysis, they expanded on the results of previous genome-wide association studies, linking identified AD susceptibility gene variants to specific DNA regulatory sequences and genes whose dysregulation is known to directly contribute to disease development. They further describe the whole-cell regulatory mechanism as a way to identify genetic regions involved in specific aspects of microglial activity.
From their investigations emerged new knowledge about the SPI1 gene, which is already well known to scientists as a major microglial transcription factor that regulates other transcription factors and gene networks, genetically linked to 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.
Dr. Roussos acknowledged that his team still has a lot of work to do to fully understand how identified genes contribute to the development and progression of Alzheimer’s disease, and how to target them with new treatments. However, he is encouraged by the results of his lab’s single-cell analyses of microglia using highly sophisticated instruments that are revealing links between different types of immune cells in and around the brain and neurodegenerative diseases unique interactions. “We are seeing very exciting results with our single-cell data,” reports Dr. Roussos, “which brings us closer to understanding the gene-driven variants and cell-specific interactions.”