**3.1 circRNAs can act as microRNA (miRNA) sponges**

Some long non-coding RNAs were described as a sponge for miRNAs, which can regulate the level or activity of miRNAs by selective sponging [33]. It was

**Figure 3.** *Functions of circRNAs.*

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

initially observed that some circRNAs have many miRNA-binding sites, leading to speculation that these molecules could act as miRNA sponges. Some circRNAs possess multiple binding sites for specific miRNAs, and some circRNAs harbor many different types of miRNA binding sites. For example, circRNA Cdr1as (ciRS-7) is extensively expressed in the mammalian brain and upregulated during neuronal development, which harbors 74 seed binding sites for miR-7 [34]. Intriguingly, miR-7 has been implicated, as a key regulator to modulate the expression of several oncogenes [35] and hold potential for slowing Parkinson's disease (PD) progression [36]. Similarly, circ-SRY (sex-determining region Y), is a master regulator of mammalian sex determination and specifically expressed in testis, which has 16 binding sites for miR-138 [37, 38]. Additionally, circHIPK3 is observed to sponge to 9 miRNAs with 18 potential binding sites [39]. cir-ITCH may act as a sponge of miR-7, miR-17, and miR-214 [40]. circHIPK3 was reported to bind to miR-124, miR-30a, and miR-558 [39, 41, 42]. So far, circRNA-miRNA axis in diseases have been expanded [43], and can be used as an advanced molecular technology to simulate or manufacture therapeutic agents, which indicates that this regulatory function of circRNAs should be a hotspot in the field of RNA. For instance, circHomer1 is upregulated in Hepatocellular carcinoma and regulates cell proliferation, migration, and invasion by inhibition of miR-1322 [44]. circTLK1 is upregulated during the acute period after focal ischemia, which can be functioned as an endogenous miR-335-3p sponge, leading to neuronal injury and neurological deficits [45]. Through deep RNA sequencing, novel\_circ\_0003012 and mmu-miR-298-3p were identified dysregulated in the hippocampus of APP/PS1 mice. Besides, novel\_circ\_0003012/mmu-miR-298-3p axis may regulate the pathological mechanism of AD by the cGPM-PKG signaling pathway [46].

### **3.2 circRNAs can interact with proteins**

The most well-known proteins interacting with RNA molecules are the RBPs. RBPs are a large class of over 2000 proteins, that interact with transcripts to participate in forming ribonucleoprotein (RNP) complexes to influence the RNA fate [47]. Many circRNAs are predicted to interact with RBPs, although bioinformatic analyses of circRNA sequences revealed very little enrichment in binding sites of RBPs [48]. Human antigen R (HuR), an extensively studied RBP, regulates protein expression patterns by associating with a wide range of noncoding RNAs (ncRNAs), including miRNAs, long ncRNAs (lncRNAs), and circRNAs [49]. Li et al. [50] found that circPABPN1 blocked HuR binding to Atg16l1 mRNA, and represses HuR-induced ATG16L1 translation, thereby modulating Autophagy in the Intestinal Epithelium. Chen et al. [51] showed that oncogenic circAGO2 physically interacts with HuR, resulting in repression of AGO2/miRNA-mediated gene silencing during cancer progression. Quaking (QKI) is a member of the STAR family of KH domain-containing RNA-binding proteins, which is involved in pre-mRNA splicing, microRNA regulation, and formation of circRNA [52]. Gupta et al. [53] found that overexpression of Quaking 5 (Qki5) strongly attenuates doxorubicininduced apoptosis and atrophy in cardiomyocytes via regulating a set of cardiac circRNAs. Zhu et al. [54] discovered that Qki5 is significantly downregulated in Hepatocellular carcinoma tissues, leading to the reduction of circZKSCAN1. Furthermore, circ-Foxo3 was observed to function as a scaffold to regulate the expression of its binding proteins by modulating protein–protein interaction. For example, circ-Foxo3 interacts with p21 and CDK2, promoting the inhibition of CDK2 by p21, and regulating cell cycle progression [17]. circ-Foxo3 can bind to p53 and Mdm2, to promote Mdm2-induced p53 ubiquitination and subsequent degradation, resulting in increased levels of Foxo3 protein [48]. circ-Foxo3 can interact with ID-1, E2F1, FAK, and HIF1α, leading to these proteins retaining in the cytoplasm and no longer exerting their anti-senescent and anti-stress roles [55].

### **3.3 m6 A modification regulates circRNA translation**

N6-methyladenosine (m6 A), the most prevalent internal RNA modification in mammalian cells, regulates RNA transcription, processing, splicing, degradation, and translation [56–58]. m6 A modification occurs by RNA methylation on the sixth N atom of adenylate (A) in RNAs [59]. m6 A modification sites tend to be found in the stop codon and 3′ untranslated region with a consensus sequence RRACH (in which R represents A or G and H represents A, C or U) [60]. The regulation function of m6 A is consisted of three factors referred to as "writers", "erasers" and "readers" [61]. m6 A "writers" are proteins involved in the formation of the methyltransferase complex, including methyltransferase-like 3/14/16 proteins (METTL3/14/16), Wilms tumor 1-associated protein (WTAP), RNA-binding motif protein 15/15B (RBM15/15B), and Vir-like m6 A methyltransferase associated (VIRMA, also known as KIAA1429) [62, 63].

m6 A methylation is dynamic and, and can be reversed by some demethylases (erasers). Erasers include FTO and AlkB homolog 3/5 (ALKBH3/5) [63, 64]. m6 A regulates gene expression through m6 A recognition factors, known as "readers," including YT521-B homology YTH domain family (YTHDF1/2/3), YTH domain containing 1 (YTHDC1/2), heterogeneous nuclear ribonucleoproteins (HNRNPs), eukaryotic translation initiation factor 3 (eIF3), and insulin-like growth factor-2 mRNA-binding proteins 1/2/3 (IGF2BP1/2/3) [61, 65].Recent studies have identified that m6A-modified circRNAs are related with pathophysiological processes. For example, m6A-modified RNA immunoprecipitation sequencing (m6A-RIP-seq) and RNA sequencing (RNA-seq) revealed the level of m6A abundance in total circRNAs was decreased in the lens epithelium cells (LECs) from cortical type of ARCs (ARCCs), and ALKBH5 was significantly upregulated [66]. Sun et al. [67] found that.

m6A modification are present on circPVRL3, which promoted gastric cancer cell proliferation. Huang et al. [68] found that circSTAG1 can bind ALKBH5 to inhibit its nuclear entry and increase the level of m6A modification of RNA, which attenuated depressive-like behaviors.

### **4. Role of circRNAs in AD**

There is rising recognition that ncRNAs differences in the context of AD have yielded insight into the pathogenic mechanisms underlying this disease as well as biomarkers and potential therapeutic targets. Here, we provide the latest information on potential circRNAs involved in AD pathology.

### **4.1 AD pathogenesis**

Reported histopathological characteristics of AD are Aβ plaques and NFTs, composed of Aβ protein accumulation and phosphorylated tau protein (p-tau) [69].

Amyloid pathogenesis starts with altered cleavage of amyloid precursor protein (APP) by β-secretases (BACE1) and γ-secretases, leading to the production of Aβ, which is then dumped into the extracellular space [70]. Consequently, accumulating Aβ forms Aβ oligomers and gradually polymerizes into amyloid fibrils that aggregate into plaques [71]. Tau is a microtubule-associated protein in neurons and *The circRNA and Role in Alzheimer's Disease: From Regulation to Therapeutic and Diagnostic… DOI: http://dx.doi.org/10.5772/intechopen.99893*

plays an important role in maintaining the stability of microtubules [72]. Abnormal phosphorylation of tau makes it insoluble, reduces its ability to bind tubulin and promote microtubule assembly, and makes it self-associate into paired helical filament [73]. Additionally, microgliosis is consistently found around plaques in the brain [74]. This facilitates microglial activation and inflammatory response, and contributes to neuritic damage.
