‘Genes associated with myeloid cells are linked to the risk of Alzheimer’s disease.’
Myeloid Cells Play a Role in Alzheimer's Disease
The study was conducted on more than 40,000 people with or without the disease, who had innate immune cells of myeloid lineage that plays an important role in Alzheimer's disease than previously assumed.
The research team has been able to identify a network of genes which are implicated in Alzheimer's disease and expressed by myeloid cells, innate immune cells which involve microglia and macrophages.
However, the research team can identify a transcription factor PU.1, a protein that could regulate gene expression and therefore cell identity and function could be a master regulator of the gene network.
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, said, "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."
"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."
A combination of genetic approaches were used to analyze the genomes of around 14,406 Alzheimer disease patients and about 25,849 control patients who did not have the disease.
The research team had found that most of the genes which can influence the age at which Alzheimer's disease can set in were expressed in the myeloid cells.
The work was found to show SPI1 gene to be a major regulator of the network of Alzheimer's disease risk genes and could also demonstrate that the lower levels of SPI1/PU.1 gene to be associated with a later age at the onset of Alzheimer's disease.
Testing the Gene Expression
In order to test the hypothesis that SPI1 expression levels can influence expression of other Alzheimer's disease risk and microglial function. The research team has used a mouse microglial cell line and BV2 cells which can be cultured in a dish.
The research team knocked down the expression of SPI1 gene that could produce PU.1 in cells. And found that the cells had shown a lower phagocytic activity. While an overexpression of the SPI1 activity can lead to increased phagocytic activity.
Most of the Alzheimer's disease genes that are expressed in the microglia may show an altered expression in response to the manipulation of the SPI1 gene expression.
Dr. Goate said, "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."
"SPI1/PU.1 expression may be a master regulator capable of tipping the balance toward a neuroprotective or a neurotoxic microglial function."
The scientists had stressed that because of the PU.1 transcription factor that regulates most of the genes in myeloid cells, the protein by itself may not be a good therapeutic target.
However, further studies of PU.1's role in Microglia and Alzheimer's disease pathogenesis are necessary and it could reveal the likely downstream targets that can be effective in modulating the Alzheimer disease risk without any effect on microglial function.
Understanding is crucial as it could facilitate the novel therapeutic targets for a disease which does not have any cure.
- 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