Nature Genetics: New findings on microglia

Human microglia are immune cells found in the brain, and Mount Sinai researchers have an unprecedented understanding
of their genetic and molecular mechanisms.
This understanding may help shed light on how they contribute to the onset and progression of Alzheimer's
disease (AD).
The study was recently published in
the journal Nature Genetics.

The researchers collected fresh human brain tissue from biopsies or autopsies from 150 donors, through which the researchers identified 21 potential risk genes, and they highlighted one, SPI1, as a potential key regulator of
microglia and AD risk.
        

Panos Roussos, professor of psychiatry, genetics and genomic sciences and director of the Center for Disease Neurogenomics at the Icahn School of Medicine at Mount Sinai, said, "Our study is the largest analysis
of human fresh tissue microglia to date on genetic risk factors that may predispose a person to Alzheimer's.
By better understanding the molecular and genetic mechanisms involved in microglial function, we can better uncover the regulatory mechanisms
that control this function and lead to AD.
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 essential for the development and maintenance of neurons, microglia also 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 the genetic risk and progression of Alzheimer's disease, little
is known about the epigenetic mechanisms behind this process.

Most early studies used models based on animal or cell lines that did not accurately reflect the true complexity of microglial activity in the brain, which are difficult to isolate in the human brain
.
Because these risk variables often appear in non-coding regions of the genome (formerly known as "junk DNA"), which are more challenging to analyze, it is difficult to link
the genetic risk variance of AD to specific molecular functions.

The Mount Sinai team's solution was to obtain fresh brain tissue from biopsies or autopsies through a collaboration of four brain biological repositories, three of which are located at Mount Sinai and one from Rush University Medical Center/Rush Alzheimer's Center
.
Dr.
Roussos explains, "Using a total of 150 samples from these sources, we were able to isolate high-quality microglia, which provides unprecedented insights
into gene regulation by reflecting a full set of regulatory components of microglia in healthy and neurodegenerative disease patients.
"

The process compares epigenetics, gene expression, and genetic information from AD and healthy elderly patient samples, allowing researchers to fully describe how the function of human microglia
is genetically modulated.
As part of their statistical analysis, they expanded on the findings of previous genome-wide association studies to link
identified AD susceptibility gene variants to specific DNA regulatory sequences and known dysregulated genes that directly contribute to disease progression.
They further describe cell-wide regulatory mechanisms as a way to
identify genetic regions involved in specific aspects of microglial activity.

From their research, new knowledge about the SPI1 gene was discovered, and the scientists already knew that the SPI1 gene is the main microglial transcription factor, regulating other transcription factors and gene networks
associated with the AD gene.
The data the team is generating may also be 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 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 new therapies target them
.
However, he was encouraged
by the results of single-cell analysis performed by his microglia lab using highly sophisticated instruments.
These analyses reveal unique interactions
between different types of immune cells in the brain associated with neurodegenerative diseases.
"With our single-cell data, we see very exciting results, which bring us closer to understanding gene drive variation and cell-specific interactions
in genetic diseases such as Alzheimer's.
"

Reference: Genetics of the human microglia regulome refines Alzheimer's disease risk loci