Scientists shed new mild on the genetic and molecular equipment that predispose people to Alzheimer’s illness.
Human microglia are immune cells that reside within the mind, and Mount Sinai researchers have attained an unprecedented understanding of their genetic and molecular equipment. This understanding might assist make clear how they contribute to the onset and development of Alzheimer’s disease (AD). The study was recently published in the journal Nature Genetics.
Researchers found 21 prospective risk genes using fresh human brain tissue collected by biopsy or autopsy from 150 donors, and they highlighted one, SPI1, as a potential key regulator of microglia and AD risk.
“Our study is the largest human fresh-tissue microglia analysis to date of genetic risk factors that might predispose someone to Alzheimer’s disease,” says senior author Panos Roussos, MD, Ph.D., Professor of Psychiatry, and Genetic and Genomic Sciences, at the Icahn School of Medicine at Mount Sinai and Director of the Center for Disease Neurogenomics. “By better understanding the molecular and genetic mechanisms involved in microglia function, we’re in a much better position to unravel the regulatory landscape that controls that function and contributes to AD. That knowledge could, in turn, pave the way for novel therapeutic interventions for a disease that currently has no effective treatments.”
In addition to being crucial for the development and maintenance of neurons, microglia play a major role in the immune response in the brain. Although prior research, including some from Mount Sinai, has shown that microglia are important for the genetic risk to and progression of Alzheimer’s disease, little is understood about the epigenetic mechanisms behind how this happens.
The majority of earlier research has either employed animal- or cell-line-based models, which do not accurately represent the true complexity of microglia activity in the brain since microglia are difficult to isolate inside the human brain. Because these risk variables are frequently found in the non-coding region of the genome (formerly known as “junk DNA”), which is more challenging to analyze, it has been difficult to link genetic risk variance for AD to specific molecular function.
The Mount Sinai team’s solution was to access fresh brain tissue from biopsies or autopsies made possible by a collaboration between four brain bio-depositories, three at Mount Sinai and the other 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, which provided unprecedented insights into genetic regulation by reflecting the entire set of regulatory components of microglia in both healthy and neurodegenerative patients,” explains Dr. Roussos.
That process—comparing epigenetic, gene expression, and genetic information from the samples of both AD and healthy aged patients—allowed researchers to comprehensively describe how microglia functions are genetically regulated in humans. As part of their statistical analysis, they expanded the findings of prior genome-wide association studies to link identified AD-predisposing genetic variants to specific DNA regulatory sequences and genes whose dysregulation is known to directly contribute to the development of the disease. They further described the cell-wide regulatory mechanisms as a way of identifying genetic regions involved in specific aspects of the microglial activity.
From their investigation emerged new knowledge about the SPI1 gene, already known to scientists, as the main microglial transcription factor regulating a network of other transcription factors and genes that are genetically linked to AD. Data the team is generating could also be important to 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 concedes that much work remains for his team to fully understand how the identified genes contribute to the development and progression of Alzheimer’s disease, and how they could be targeted with new therapeutics. He is greatly encouraged, though, by the results of single-cell analysis by his lab of microglia using highly sophisticated instruments that are uncovering the unique interactions between different types of immune cells in the brain and its periphery that are related to neurodegenerative disease. “We’re seeing very exciting results through our single-cell data,” Dr. Roussos reports, “and that’s bringing us ever closer to understanding the genetically driven variations and cell-specific interactions of inheritable diseases like Alzheimer’s.”
Reference: “Genetics of the human microglia regulome refines Alzheimer’s disease risk loci” by Roman Kosoy, John F. Fullard, Biao Zeng, Jaroslav Bendl, Pengfei Dong, Samir Rahman, Steven P. Kleopoulos, Zhiping Shao, Kiran Girdhar, Jack Humphrey, Katia de Paiva Lopes, Alexander W. Charney, Brian H. Kopell, Towfique Raj, David Bennett, Christopher P. Kellner, Vahram Haroutunian, Gabriel E. Hoffman, and Panos Roussos, 5 August 2022, Nature Genetics.