miR-146a Dysregulates Energy Metabolism During Neuroinflammation

Alzheimer's disease (AD) and other neurodegenerative diseases are characterized by chronic neuroinflammation and a reduction in brain energy metabolism. An important role has emerged for small, non-coding RNA molecules known as microRNAs (miRNAs) in the pathophysiology of many neurodegenerative disorders. As epigenetic regulators, miRNAs possess the capacity to regulate and fine tune protein production by inhibiting translation. Several miRNAs, which include miR-146a, are elevated in the brain, CSF, and plasma of AD patients. miR-146a participates in pathways that regulate immune activation and has several mRNA targets which encode for proteins involved in cellular energy metabolism. An additional role for extracellular vesicles (EVs) has also emerged in the progression AD, as EVs can transfer functionally active proteins and RNAs from diseased to healthy cells. In the current study, we exposed various cell types present within the CNS to immunomodulatory molecules and observed significant upregulation of miR-146a expression, both within cells and within their secreted EVs. Further, we assessed the effects of miR-146a overexpression on bioenergetic function in primary rat glial cells and found significant reductions in oxidative phosphorylation and glycolysis. Lastly, we correlated miR-146a expression levels within various regions of the AD brain to disease staging and found significant, positive correlations. These novel results demonstrate that the modulation of miR-146a in response to neuroinflammatory stimuli may mediate the loss of mitochondrial integrity and function in cells, thereby contributing to the progression of beta-amyloid and tau pathology in the AD brain. Multiple inflammatory stimuli can upregulate miRNA-146a expression within neurons, mixed glial cells, and brain endothelial cells, which is either retained within these cells or released from them as extracellular vesicle cargo. The upregulation of miR-146a disrupts cellular bioenergetics in mixed glial cells. This mechanism may play a critical role in the neuroinflammatory response observed during Alzheimer's disease.