**4.2 A**β **production and clearance in AD**

Except for some antisense transcripts and microRNAs involved in accumulation, oligomerization, aggregation and formation of Aβ plaques, recent studies have shown that circRNAs may play a role in the of production and clearance Aβ [75, 76]. For example, circHDAC9 acted as a miR-138 sponge, decreasing miR-138 expression, Inhibiting the production of Aβ, and alleviating synaptic and learning/memory deficits in APP/PS1 mice. Moreover, circHDAC9 was remarkably decreased in the serum of both mild cognitive impairment and AD patients [77]. Shi et al. [78] found that ciRS-7 promotes the expression of UCHL1, reduces the protein levels of APP and BACE1 by promoting their degradation, and inhibits translation of NF-κB, thereby reducing the generation of Aβ. Shi et al. [79] demonstrated that circAβ-a, containing the corresponding Aβ coding sequence, served as a template for the synthesis of a novel Aβ-containing Aβ175 polypeptide in both cultured cells and human brain. Utilizing deep RNA sequencing, Zhang et al. [80] observed that there are 235 significantly dysregulated circRNA transcripts in a 7-month-old senescence-accelerated mouse prone 8. Additionally, circRNA-related ceRNA networks in this AD mouse model were mainly involved in the regulation of Aβ clearance.

### **4.3 Neuroinflammation in AD**

A number of studies have proven that in addition to Aβ and NFTs, neuroinflammation is exhibited in the brains of AD patients and contributes to the pathogenesis of this disease [81, 82]. Not only Aβ can activate the microglia, but also Tau protein can trigger inflammation through interaction with microglia. Due to the accumulation of Aβ and hyperphosphorylation of Tau, microglia are persistently activated, which produce inflammatory cytokines and chemokines, contributing to the neuroinflammation process [81, 83]. For instance, TNF-α can stimulate γ-secretase activity, which results in increased levels of Aβ and the following cognitive decline in AD [84]. IL-1 increases generation of Aβ and phosphorylation of tau protein, leading to dysfunction of the cholinergic system [85]. Studies have shown that CCL2 and CCL5 expression are increased in the AD brain. Up to now, there are few reports in this field. Wang et al. [86] found that in OGD-activated microglia, circPTK2 regulates neuronal apoptosis via sponging miR-29b. it can be inferred that circRNAs may be involved in the activation of AD microglia. One study on circRNAs involved in neuroinflammation indicates that circ\_0000950 inhibits miR-103 expression and increases prostaglandin-endoperoxide synthase 2 (PTGS2) expression in AD models. Moreover, circ\_0000950 promotes neuron apoptosis, neurite outgrowth, and affects the level of IL-1β, IL-6 and TNF-α via directly sponging miR-103 in AD [87].

### **4.4 Oxidative stress in AD**

Emerging evidences demonstrate that oxidative stress has been recognized as a contributing factor in the progression of AD. It has been confirmed that elevated levels of Aβ are associated with increased levels of oxidation products, and protein and lipid oxidation was observed in brain regions rich in Aβ [88, 89]. Moreover,

due to the role of protein Tau both in the modulation microtubule dynamics and morphology and physiology of neurons, Tau alteration would constitute to a target for oxidative stress in AD [90, 91]. Recently, important regulatory roles of some circRNAs in the oxidative stress have been identified. Previous studies have shown that panax notoginseng saponins (PNS) could protect neurons in AD brain from oxidative stress damage injury via attenuating the production of 8-hydroxydeoxyguanosine (8-OHdG), enhanceing the expressions and activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-PX) [92]. Through circRNA Microarray, it was found that PNS treatment leads to five circRNAs upregulation and two circRNAs downregulation. Next, mmu\_circRNA\_013636 and mmu\_circRNA\_012180 were selected, and GO and KEGG analyses were showed that mmu\_circRNA\_013636 and mmu\_circRNA\_012180 were involved in AD-associated biological process [93]. Based on these results, the mmu\_circRNA\_013636 and mmu\_circRNA\_012180 may be associated with the mechanisms by which PNS attenuates AD progression, and may be highly related to the regulation of oxidative stress. Zhu et al. [94] found that the expression level of circular ribonucleic acid 0001588 was suppressed in model of AD, which promoted cell growth, reduced levels of lactate dehydrogenase, caspase-3, and caspase-9. Besides, circular ribonucleic acid 0001588 reduced reactive oxygen species production via activation of the silent information regulator 1 pathway.
