Abstract
Recent studies have demonstrated circular RNAs (circRNAs) to be widely expressed and to have important physiological functions. However, the expression, regulation, and function of circRNAs in neuroglial cells are unknown. Herein, we characterized the expression, regulation, and function of circRNAs in astrocytes. Astrocyte circRNAs were identified by computational analysis of newborn SD rat primary astrocytes cultured with 20 g/L D-galactose. In this manner, 7376 circRNAs were identified, among which most circRNAs (5754) were derived from annot_exons, whereas 27 were antisense, 853 were exon/intron, 329 were intergenic, 41 were intronic, and 372 were one exon. Among these, circNF1-419 was demonstrated to regulate autophagy, in over-expressing circNF1-419 transfected astrocytes, through the PI3K-I/Akt-AMPK-mTOR and PI3K-I/Akt-mTOR signaling pathways. An adenovirus associated virus packaging system (virus titer 1 ×1012), over-expressing circNF1-419 and injected into mouse cerebral cortex, showed autophagy enhancing activity by binding the proteins Dynamin-1 and Adaptor protein 2 B1 (AP2B1). This binding regulated aging markers (p21, p35/25, and p16) and inflammatory factors (TNF-α and NF-κB), and reduced the expression of Alzheimer’s disease marker proteins (Tau, p-Tau, Aβ1-42, and APOE), which delayed senile dementia. Transcriptome analysis of the brain showed that circNF1-419 improved other signaling pathways, especially those related to the synapses of SAMP8 mice. These findings provide novel insights into circNF1-419 and its potential usefulness for the diagnosis and treatment of dementia by regulating Dynamin-1 and AP2B1 mediated autophagy.
Highlights
As the Chinese population ages, demographics will change such that by the end of 2020 the number of people over 60 years of age will be 19.3 percent and by 2050 greater than 38 percent of the total population
These findings provide novel insights into circNF1-419 and its potential usefulness for the diagnosis and treatment of dementia by regulating Dynamin-1 and Adaptor protein 2 B1 (AP2B1) mediated autophagy
Expression of aging biomarkers, P21Cip1/Waf1 and P16INK4a, were increased (Figure 1O). These results demonstrate D-galactose to induce the senescence of astrocytes after two generations of cell culture (Figure 1A–1O)
Summary
As the Chinese population ages, demographics will change such that by the end of 2020 the number of people over 60 years of age will be 19.3 percent and by 2050 greater than 38 percent of the total population. Glial cells participate in almost all nervous system activities from the embryonic stage to the aged brain. They are involved in central nervous system functions including; synaptic transmission, nerve tissue repair, regeneration, immunity, and aging. Clearance of senescent glial cells can prevent taudependent pathology and cognitive decline [16] These results suggest that targeting senescent cells could provide a therapeutic avenue for the treatment of Alzheimer’s disease (AD). A targeted circRNA over-expression system was used to assess physiological function and the targeted effects of circRNA on the aging process In this manner, new targets were assessed for the diagnosis and treatment of age-related brain disease
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