SMALL NON-CODING RNA DYSREGULATION IN THE MICROGLIA FROM A MOUSE MODEL OF DOWN SYNDROME

Microglia are the brain’s resident immune cells and regulate a wide range of mechanisms critical for neuronal activity and cognitive functions. Down Syndrome (DS), is a genetic disorder caused by trisomy of human chromosome 21 (Hsa21), characterized by intellectual disability and multiple health issues, including immune system alterations. Microglia overactivation is present in both individuals with DS and DS mouse models such as Dp(16)1Yey/+ (Dp16) mice, where it correlates with impaired neuronal function and cognitive deficits. Moreover, microglial inflammatory response is tightly regulated by small non-coding RNAs such as microRNAs (miRNA), while others such as Piwi-interacting RNAs (piRNA), tRNA derived fragments (tRFs) have not been explored, potentially representing novel targets for therapeutic interventions.
In this study, we aimed to investigate the contribution of small non-coding RNAs to the dysregulation of microglia associated to DS. Using the Dp16 mouse model we characterized small non-coding RNA expression in microglia to shed light to their role in sustaining chronic and acute inflammatory states in DS. As entry point, we analyzed miRNAs in FACS-sorted microglia isolated from Dp16 and wild-type mice at postnatal day 21 (P21) and identified several miRNAs that were differentially expressed. Interestingly, many of these miRNAs were also dysregulated in microglia from mouse models of acute neuroinflammation, supporting a correlation with a sustained inflammatory microglial state in DS, which may affect neuronal function.
Our findings indicate that small non-coding RNA dysregulation may drive microglial dysfunction in DS, identifying these pathways as potential diagnostic molecules and therapeutic targets.