<i>Argonaute 2</i> in Neurons is essential for healthy Blood Brain Barrier Formation

Our study highlights the crucial role of Ago2 in glutamatergic neurons, leading to postnatal lethality due to disruption in the neurovascular unit (NVU) and neuronal positioning in the developing cortex. Surprisingly, the absence of Ago2 only affected postnatal survival when removed from glutamatergic, not GABAergic neurons. Through single-cell analysis, we found that loss of Ago2 in this specific subset led to impaired synapse formation and endothelial cell connections, resulting in neuroinflammation. Dysregulation of the microRNA pathway and upregulation of Pten were observed, and de-repression of Pten in Ago2-deficient mice partially rescued the blood brain barrier (BBB) and increased survival CONCLUSION: Our study identifies a vital neuronal population where miRNA function is essential for blood-brain barrier formation. The loss of functional Ago2 in this neuronal population leads to BBB collapse and neuroinflammation. These observations warrant studies to be conducted in subjects with vascular dementia to investigate if mutations exist in functional Ago2 that correlate with Ago2 syndrome.