MiR-135a-5p as a Target to Induce Greater Neurogenesis

Neurogenesis is the creation of new neurons in the brain, followed by their integration into neural circuits. It is generally agreed upon in the research community that increasing the degree of neurogenesis that takes place in the aging brain is a desirable therapeutic goal, particularly since this process appears to decline with age. Greater neurogenesis should increase both resilience to injury and cognitive function. A great deal of work takes place in this part of the field, though it is a complicated business and is not progressing towards practical therapies anywhere near as rapidly as desired. The research here is a representative example of the sort of work that has taken place over the past decade: numerous regulatory molecules have been identified, and proposed as a basis for intervention. Whether anything comes of this one remains to be seen.

In most mammalian species, the postnatal subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) maintains a population of neural precursor cells (NPCs) retaining the lifelong capability to generate new neurons and astrocytes. However, this process inexorably declines with age, and this decline has been correlated with the loss of cognitive abilities and the occurrence of several brain pathologies. Currently, many translational concepts for preserving cognitive abilities in the aging brain thus aim at sustaining, or even increasing, the potential for cognitive plasticity and flexibility that is contributed by the adult-generated neurons.

Environmental enrichment and physical activity (e.g., voluntary running in a wheel) potentiate adult neurogenesis in rodents. The positive response of adult neurogenesis to these stimuli is maintained into old age and counteracts the age-associated cognitive decline in rodents and likely in humans. However, the cellular and molecular mechanisms underlying homeostasis of adult neurogenesis and its response to environmental stimuli remain elusive. We hypothesize that exploiting these mechanisms is relevant for preventing age-related cognitive decline in humans and that our animal models can contribute to providing evidence-based recommendations for an active lifestyle for successful aging.

MicroRNAs (miRNAs) are small noncoding RNAs which, by post-transcriptional repression of hundreds of target messenger RNAs (mRNAs) in parallel, tune the entire cell proteome. The functional synergism of few miRNAs achieves gene regulation essential for proliferation, cell fate determination, and survival. Interestingly, running stimulates hippocampal NPC proliferation and alters miRNA expression in rodents. Hence, we hypothesize that investigating miRNAs involved in running-induced neurogenesis would allow the identification of the most prominent pathways that constrain NPC proliferative potential in the adult mouse hippocampus.

Here, we show that exercise increases proliferation of neural precursor cells (NPCs) of the mouse dentate gyrus (DG) via downregulation of microRNA 135a-5p (miR-135a). MiR-135a inhibition stimulates NPC proliferation leading to increased neurogenesis, but not astrogliogenesis, in DG of resting mice, and intriguingly it re-activates NPC proliferation in aged mice. We identify 17 proteins (11 putative targets) modulated by miR-135 in NPCs. MiR-135 is the first noncoding RNA essential modulator of the brain's response to physical exercise. Prospectively, it might represent a novel target of therapeutic intervention to prevent pathological brain aging.

Link: https://doi.org/10.1016/j.stemcr.2019.04.020


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