Alzheimer's disease risk linked to a network of genes associated with myeloid cells

June 26, 2017
PET scan of a human brain with Alzheimer's disease. Credit: public domain

Many genes linked to late-onset Alzheimer's disease (AD) are expressed in myeloid cells and regulated by a single protein, according to research conducted at the Icahn School of Medicine at Mount Sinai and published June 19 in the journal Nature Neuroscience.

Mount Sinai researchers led an international, genome-wide study of more than 40,000 people with and without the disease and found that innate immune cells of the lineage play an even more central role in Alzheimer's disease pathogenesis than previously thought.

Specifically, the research team identified a network of that are implicated in AD and expressed by , innate immune cells that include microglia and macrophages. Furthermore, researchers identified the transcription factor PU.1, a protein that regulates gene and, thus, cell identity and function, as a master regulator of this gene network.

"Our findings show that a large proportion of the genetic risk for late-onset AD is explained by genes that are expressed in myeloid cells, and not other cell types," says Alison Goate, DPhil, Professor of Neuroscience and Director of The Ronald M. Loeb Center for Alzheimer's Disease at the Icahn School of Medicine at Mount Sinai and principal author of the study. "Dysregulation of this network is certainly a cause of Alzheimer's, but we have more work to do to better understand this network and regulation by PU.1, to reveal promising therapeutic targets."

Using a combination of genetic approaches to analyze the genomes of 14,406 AD patients, and 25,849 control patients who do not have the disease, researchers found that many genes which are known to influence the age at which AD sets in, are expressed in myeloid cells. This work pinpointed SPI1, a gene that encodes the transcription factor PU.1, as a major regulator of this network of AD risk genes and demonstrated that lower levels of SPI1/PU.1 are associated with later age at onset of AD.

To test the hypothesis that SPI1 expression levels influence expression of other AD risk genes and microglial function, the researchers used a mouse microglial cell line, BV2 cells that can be cultured in a dish. When researchers knocked down expression of SPI1, the gene that produces PU.1 in cells, they found that the cells showed lower phagocytic activity (engulfment of particles), while overexpression of SPI1 led to increased phagocytic activity. Many other AD genes expressed in microglia also showed altered expression in response to this manipulation of SPI1 expression.

"Experimentally altering PU.1 levels correlated with phagocytic activity of mouse microglial cells and the expression of multiple AD genes involved in diverse biological processes of myeloid cells," says Dr. Goate. "SPI1/PU.1 expression may be a master regulator capable of tipping the balance toward a neuroprotective or a neurotoxic microglial function."

The researchers stress that because the PU.1 transcription factor regulates many genes in myeloid , the protein itself may not be a good therapeutic target. Instead, further studies of PU.1's role in microglia and AD pathogenesis are necessary, as they may reveal promising downstream targets that may be more effective in modulating AD risk without broad effects on microglial function. Increased understanding is crucial to facilitating the development of novel therapeutic targets for a disease that currently has no cure.

Explore further: Phagocytes in the brain—good or bad?

More information: Kuan-lin Huang et al. A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease, Nature Neuroscience (2017). DOI: 10.1038/nn.4587

Related Stories

Phagocytes in the brain—good or bad?

May 31, 2017
The role of microglial cells in neurodegenerative disease is not fully understood. But new results from researchers in Munich and Basel suggest that stimulation of this arm of the immune system might well delay the onset ...

Brain's immune cells linked to Alzheimer's, Parkinson's, schizophrenia

May 31, 2017
Scientists have, for the first time, characterized the molecular markers that make the brain's front lines of immune defense—cells called microglia—unique. In the process, they discovered further evidence that microglia ...

Skin stem cells used to generate new brain cells

April 25, 2017
Using human skin cells, University of California, Irvine neurobiologists and their colleagues have created a method to generate one of the principle cell types of the brain called microglia, which play a key role in preserving ...

Role of bone marrow-derived stem cells in acute myeloid leukemia at time of diagnosis

May 4, 2017
On diagnosis of acute myeloid leukemia, the mesenchymal stem cells (MSCs) in bone marrow often show alterations in gene and protein expression, proliferation capacity, and function, but whether these are a cause or result ...

Innate immune landscape in glioblastoma patient tumors

February 25, 2016
Glioblastoma is an extremely aggressive brain tumor with limited treatment options. Recent progress in using immunotherapy-based treatment options in other tumor types has spurred interest in developing approaches that might ...

Recommended for you

Cognitive cross-training enhances learning, study finds

July 25, 2017
Just as athletes cross-train to improve physical skills, those wanting to enhance cognitive skills can benefit from multiple ways of exercising the brain, according to a comprehensive new study from University of Illinois ...

Lutein may counter cognitive aging, study finds

July 25, 2017
Spinach and kale are favorites of those looking to stay physically fit, but they also could keep consumers cognitively fit, according to a new study from University of Illinois researchers.

Zebrafish study reveals clues to healing spinal cord injuries

July 25, 2017
Fresh insights into how zebrafish repair their nerve connections could hold clues to new therapies for people with spinal cord injuries.

Brain stimulation may improve cognitive performance in people with schizophrenia

July 24, 2017
Brain stimulation could be used to treat cognitive deficits frequently associated with schizophrenia, according to a new study from King's College London.

New map may lead to drug development for complex brain disorders, researcher says

July 24, 2017
Just as parents are not the root of all their children's problems, a single gene mutation can't be blamed for complex brain disorders like autism, according to a Keck School of Medicine of USC neuroscientist.

Bird songs provide insight into how developing brain forms memories

July 24, 2017
Researchers at the University of Chicago have demonstrated, for the first time, that a key protein complex in the brain is linked to the ability of young animals to learn behavioral patterns from adults.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.