New Neurons in Aging Brains: Molecular Control by Small Non-Coding RNAs

Abstract

Adult neurogenesis generates functional neurons from neural stem cells present in specific brain regions. It is largely confined to two main regions: the subventricular zone of the lateral ventricle, and the subgranular zone of the dentate gyrus (DG), in the hippocampus. With age, the function of the hippocampus and particularly the DG is impaired. For instance, adult neurogenesis is decreased with aging, in both proliferating and differentiation of newborn cells, while in parallel an age-associated decline in cognitive performance is often seen. Surprisingly, the synaptogenic potential of adult-born neurons is only marginally influenced by aging. Therefore, although proliferation, differentiation, and synaptogenesis of adult-born new neurons in the DG are closely related to each other, they are differentially affected by aging. In this review we discuss the crucial roles of a novel class of recently discovered modulators of gene expression, the small non-coding RNAs, in the regulation of adult neurogenesis. Multiple small non-coding RNAs are differentially expressed in the hippocampus. In particular a subgroup of the small non-coding RNAs, the microRNAs, fine-tune the progression of adult neurogenesis. This makes small non-coding RNAs appealing candidates to orchestrate the functional alterations in adult neurogenesis and cognition associated with aging. Finally, we summarize observations that link changes in circulating levels of steroid hormones with alterations in adult neurogenesis, cognitive decline, and vulnerability to psychopathology in advanced age, and discuss a potential interplay between steroid hormone receptors and microRNAs in cognitive decline in aging individuals.

Neural stem cell- and neurogenesis-related gene expression profiles in the young and aged dentate gyrus

“…For example, target mRNA recognition by the miRNA leads to a decrease in the abundance of proteins encoded by the target mRNA. This has been explained by several mechanisms including posttranscriptional degradation of the target, translational repression, and deadenylationdependent target decay through partially complementary miRNA target sites in mRNA untranslated regions (Maroney et al 2006;Petersen et al 2006;Schouten et al 2012). Thus, it is likely that one or more of the above posttranscriptional modifications underlie the discrepancy observed in the measured gene expression and protein concentration (Lindner and Demarez 2009).…”

Novel Stroke Therapeutics: Unraveling Stroke Pathophysiology and Its Impact on Clinical Treatments

“…Multiple pathways induce neurogenesis, including those triggered by numerous neurotrophic and growth factors such as GDNF, BDNF, granulocyte colony-stimulating factor (G-CSF), and insulin growth factor (IGF-1) (Kobayashi et al, 2006;Dempsey et al, 2003). Alternative mechanisms of increasing endogenous NPC proliferation include anti-inflammatory drugs like indomethacin, non-coding RNA, and hormones such as erythropoietin (Hoehn et al, 2005; Schouten et al, 2012; Wang et al, 2004). Delivering G-CSF and IGF-1 to alter key survival pathways such as the phosphoinositide 3-kinase-Akt pathway are able to reduce NPC death (Lee et al, 2006).…”

Neurorestoration after stroke

“…27,41,60,80,91,97,127,131,136,149,152 Alternative strategies to increase NPC proliferation include antiinflammatory drugs, noncoding RNAs, and hormones such as erythropoietin and growth hormone. 71,137,151 A complementary approach strives to limit NPC death through administration of G-CSF and insulin-like growth factor–1 to alter key survival pathways. 96 Inhibition of p53 and use of cyclosporine have also been studied as strategies to extend NPC survival.…”