AP2B1
AP-2 complex subunit beta (AP105B) (Adaptor protein complex AP-2 subunit beta) (Adaptor-related protein complex 2 subunit beta) (Beta-2-adaptin) (Beta-adaptin) (Clathrin assembly protein complex 2 beta large chain) (Plasma membrane adaptor HA2/AP2 adaptin beta subunit) [ADTB2] [CLAPB1]
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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, [i]circNF1-419[/i] was demonstrated to regulate autophagy, in over-expressing [i]circNF1-419[/i] 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 ×10 ), over-expressing [i]circNF1-419[/i] 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, Aβ , and APOE), which delayed senile dementia. Transcriptome analysis of the brain showed that [i]circNF1-419[/i] improved other signaling pathways, especially those related to the synapses of SAMP8 mice. These findings provide novel insights into [i]circNF1-419[/i] and its potential usefulness for the diagnosis and treatment of dementia by regulating Dynamin-1 and AP2B1 mediated autophagy.
MeSH Terms
- Adaptor Protein Complex beta Subunits
- Aging
- Alzheimer Disease
- Animals
- Astrocytes
- Autophagy
- Cellular Senescence
- Dynamin I
- Genes, Neurofibromatosis 1
- Mice
- RNA, Circular
- Rats
- Rats, Sprague-Dawley
Keywords
- aging
- astrocyte
- autophagy
- biological function
- circular RNA
Aging is an inevitable part of life for humans, and slowing down the aging process has become a main focus of human endeavor. Here, we applied a systems biology approach to construct protein-protein interaction networks, gene regulatory networks, and epigenetic networks, i.e. genetic and epigenetic networks (GENs), of elderly individuals and young controls. We then compared these GENs to extract aging mechanisms using microarray data in peripheral blood mononuclear cells, microRNA (miRNA) data, and database mining. The core GENs of elderly individuals and young controls were obtained by applying principal network projection to GENs based on Principal Component Analysis. By comparing the core networks, we identified that to overcome the accumulated mutation of genes in the aging process the transcription factor JUN can be activated by stress signals, including the MAPK signaling, T-cell receptor signaling, and neurotrophin signaling pathways through DNA methylation of BTG3, G0S2, and AP2B1 and the regulations of mir-223 let-7d, and mir-130a. We also address the aging mechanisms in old men and women. Furthermore, we proposed that drugs designed to target these DNA methylated genes or miRNAs may delay aging. A multiple drug combination comprising phenylalanine, cholesterol, and palbociclib was finally designed for delaying the aging process.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Biomarkers
- Computational Biology
- DNA Methylation
- Epigenomics
- Female
- Gene Expression Profiling
- Gene Regulatory Networks
- Humans
- Leukocytes, Mononuclear
- Male
- MicroRNAs
- Middle Aged
- Signal Transduction
- Young Adult
Keywords
- DNA methylation
- Gerotarget
- anti-ageing drugs
- genetic-and-epigenetic network
- human aging
- microRNAs