**4.5 Autophagy in AD**

Substantial studies reveal that deficits in autophagy are involved in AD pathogenesis. Defective autophagy and mitophagy, which is responsible for synaptic dysfunction and cognitive deficits, are triggered by Aβ and Tau accumulation [95]. Recently, several reports have described potential roles for circRNAs in autophagosome assembly or vesicular transport-mediated pathways [96]. For example, Chen et al. [97] found that circNF1–419 regulates autophagy through PI3K-I/Akt-AMPKmTOR and PI3K-I/Akt–mTOR signaling pathways, and reduces the expression of AD marker proteins Tau, p-Tau, Aβ1–42, and APOE in AD-like mice. Using circRNA microarray, GO analysis revealed that mmu\_circRNA\_017963 is highly associated with autophagosome assembly, exocytosis, apoptotic process, transport and RNA splicing in an AD mouse model. Moreover, KEGG pathway analysis indicated that mmu\_circRNA\_017963 was strongly related with synaptic vesicle cycle, spliceosome, glycosaminoglycan, and SNARE interactions in vesicular transport [98]. All of these biological processes are reported to play an important role in the development of AD [98, 99].

### **4.6 Therapeutic targets and diagnostic biomarkers in AD**

Due to the high stability with covalently closed continuous loop, circRNAs are not sensitive to ribonucleases, such as RNase R, and have a longer half-life compared to linear RNAs [100]. An accumulating number of studies have shown that dysregulated circRNAs are significantly related to AD, which are considered to be potential biomarkers. For instance, Dube et al. [101] found that circRNA expression significantly associated with the diagnosis of AD, the severity of clinical dementia, and the severity of neuropathology. Lo et al. [102] profiled circRNA expression at different AD stages in brain samples from four brain regions: anterior prefrontal cortex, superior temporal lobe, parahippocampal gyrus and inferior frontal gyrus using a public RNA-sequencing dataset. There are 147 differentially expressed circRNAs to be found in the four regions, and most circRNAs in AD patients with severe symptoms are enriched in the parahippocampal gyrus. This

*The circRNA and Role in Alzheimer's Disease: From Regulation to Therapeutic and Diagnostic… DOI: http://dx.doi.org/10.5772/intechopen.99893*

finding could help to distinguish the disease severity of patients, and further implying that circRNAs may serve as biomarkers of AD. In addition, circRNAs can stably exist in blood plasma and cerebrospinal fluid. Liu et al. [103] discovered that hsa\_circ\_0003391 is significantly downregulated in the peripheral blood, and closely related to clinical features of patients with AD. By microarray, Li et al. [104] found 112 circRNAs were upregulated and 51 circRNAs were downregulated in cerebrospinal fluid of AD patients. Among the up-regulated circRNAs, circ-AXL was negatively correlated with Aβ42 and positively correlated with t-Tau and p-tau, suggesting it hold the clinical value for predicting disease risk and disease severity of AD. Moreover, research on circRNAs sponges may help to design and develop effective artificial sponges to regulate disease progression. As a stable and effective miRNA inhibitor, artificial miRNA sponge technology may be a new strategy for RNA gene therapy in the future.

### **5. Conclusions and future perspectives**

circRNAs have gained increased attention because of their involvement in different biological processes. With the rapid progress of high throughput sequencing and bioinformatics technology, multiple circRNAs have demonstrated to be closely associated with various diseases. Although the function and modulation of circRNA has not been clearly understood, studies have started to excavate effect of AD-related circRNAs, which brought us many surprising findings. As a class of stable RNA, circRNAs have natural advantages and may play vital roles as therapeutic targets and prognostic factors for AD. Recently, with the emergence of CRISPR-Cas13d screening tools [105], lipid nanoparticle (LNP) delivery system [106], the in vitro engineered preparation of circRNA can be realized, and make the application of circRNA in clinical therapy possible. In addition, Lavenniah et al. [107] constructed a circmiR sponge targeting the known cardiac pro-hypertrophic miRs-132 and miRs-212, and delivered it to cardiomyocytes *in vivo by* Adeno-associated viruses (AAVs). Subsequently, the hypertrophic characteristics of the disease were attenuated, thus supporting the therapeutic potential of Engineered circRNAs. However, there are some some questions that deserve attention. Firstly, most of the current studies on circRNAs rely on the results of RNA-sequencing and microarray. There are significant differences between the output of different algorithms, emphasizing that these circRNAs need urther validation. Secondly, many circRNAs have been identified to be differentially expressed at different developmental stages, but the precise mechanisms are still not clear. Thirdly, at present, most studies on circRNAs mainly focus on miRNA sponge, and there are few studies on other mechanisms. In conclusion, circRNA research is still in its infancy and their molecular mechanism and functional role need to be further elucidated. circRNAs are widely involved in the regulation of physiological and pathophysiological processes, and may have the potential to be new biomarkers and novel therapeutic targets.
