In a large genome-wide study of more than 40,000 people, recently published in Nature Neuroscience, researchers found that myeloid cells, involved in the innate immune system of the brain, play an even more central role in Alzheimer's disease than previously thought. Especially with regard to the age of onset this network seems to play an important role.
The key driver in this mechanism is a protein called PU.1, encoded by the SPI1 gene, which plays a critical role in myeloid cell development and impacting key Alzheimer related dysfunctions such as phagocytic clearance of β-amyloid, apoptotic cells, myelin debris and lipoproteins. Also SPI1 mouse knockout models affected the expression of mouse orthologs of many AD risk genes and the phagocytic activity of mouse microglial cells.
The central role of SPI1 in this immune regulatory network is an important step forward. However, as the researchers note, much additional research is required to understand it’s role in Alzheimer’s. Especially important is the fact that SPI1 plays such a central role that it is unlikely to be a safe therapeutic target. A quick search in the Euretos Knowledge Platform shows that SPI1 acts as a transcription factor for 645 downstream genes:
Figure 1: Visualisation of the genes affected by SPI1(source: Euretos Knowledge Platform)
Given the number of downstream interactions, another downstream gene within this network needs to be found which is more suitable as a potential drug target. Using the Euretos Analytics application, 38 potential targets were identified that are regulated by SPI1, expressed in the brain, related to Alzheimer’s disease and expressed in myeloid cells:
Figure 2: Genes regulated by SPI1, expressed in the brain, related to Alzheimer’s disease and expressed in myeloid cells (source: Euretos Knowledge Platform)
Out of these 38 potential downstream SPI1 targets, many are themselves key players in downstream regulatory networks. Further analysis shows that 12 of these candidate targets have more limited interactions making them better potential drug candidates:
This list of 12 genes regulated by SPI1, expressed in the brain, related to Alzheimer’s disease, expressed in myeloid cells and having limited downstream effects, may offer a good starting point for further research in identifying a potential drug target based on the immunresponse within the brain.
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About this series - The purpose of the Euretos Research Note series is to provide a data analytics perspective on recent life sciences publications. The series focuses on two types of questions: (1) Did the available data already point in the direction of a discovery? (2) What further research angles does the available data suggest?