RT-DOb, a switch gene for the gene pair {Csf1r, Milr1}, can influence the onset of Alzheimer’s disease by regulating communication between mast cell and microglia

Abstract

In biology, homeostasis is a central cellular phenomenon that plays a crucial role in survival. The central nervous system (CNS) is controlled by exquisitely sensitive homeostatic mechanisms when facing inflammatory or pathological insults. Mast cells and microglia play a crucial role in CNS homeostasis by eliminating damaged or unnecessary neurons and synapses. Therefore, decoding molecular circuits that regulate CNS homeostasis may lead to more effective therapeutic strategies that specifically target particular subsets for better therapy of Alzheimer’s disease (AD). Based on a computational analysis of a microarray dataset related to AD, the H2-Ob gene was previously identified as a potential modulator of the homeostatic balance between mast cells and microglia. Specifically, it plays such a role in the presence of a three-way gene interaction in which the H2-Ob gene acts as a switch in the co-expression relationship of two genes, Csf1r and Milr1. Therefore, the importance of the H2-Ob gene as a potential therapeutic target for AD has led us to experimentally validate this relationship using the quantitative real-time PCR technique. In the experimental investigation, we confirmed that a change in the expression levels of the RT1-DOb gene (the rat ortholog of murine H2-Ob) can switch the co-expression relationship between Csf1r and Milr1. Furthermore, since the RT1-DOb gene is up-regulated in AD, the mentioned triplets might be related to triggering AD.

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“…Furthermore, the area under the receiver operating characteristic (ROC) curve (AUC) is widely employed to evaluate the performance of supervised classification models 20 . In our analysis, we utilized ROC curves to assess the sensitivity and specificity of the Random Forest model.…”

“…The importance of RT-DOb /{ Csf1r , Milr1 } triplet in onset of Alzheimer’s disease has been suggested and validated in previous studies. These studies indicated the change in expression level of RT-DOb gene, as a switch gene, can disturb the communication between mast cell and microglia 19 , 20 . Another study suggested the Rps27a gene can act as a switch gene for { Il-18 , Cx3cl1 } gene pair and be associated with pathogenesis of the major neurodegenerative diseases by controlling the microglia activation 21 .…”