Gene regulation networks are complex and diverse. Recent studies examining the regulation of microRNAs (miRNAs) in AD have been relatively thorough, and mechanisms of these miRNAs have been clarified. MiRNAs are short RNAs with a length of 21–24 base pairs that play vital roles in regulating gene expression at the posttranscriptional level by binding to the 3′ untranslated region (3′-UTR) of target mRNAs to suppress their stability and translation (Cannell et al., 2008). In addition, several target mRNAs contain multiple binding sites for different ncRNAs, suggesting that individual mRNAs are regulated by many ncRNAs.

PIWI-interacting RNAs (piRNAs) are ncRNAs with 24–32 nts that interact with piwi proteins and function in a complex to regulate cellular activities through RNA silencing. Most piRNAs are distributed in mammalian germline cells. Recent studies have found piRNAs is found in the brains of multiple species. However, piRNAs are poorly conserved, even between closely related species, and are tissue specific. Therefore, relatively little knowledge is available on the potential roles of piRNAs in species and/or the brain, even in neurodegenerative diseases (Wakisaka and Imai, 2019).

The mechanism of PIWI-piRNA function relies on the specific sequence of the piRNA that recognizes its target genes through base-pair complementarity, silencing the target mRNA at both the transcriptional and posttranscriptional levels. The PIWI protein is an effector in the piRNA-mRNA pathway. Genes are often silenced at the transcriptional level through the induction of repressive chromatin modifications at genomic target loci and via de novo DNA methylation (Figure 1Ai) (Kim, 2019). Gene silencing at the posttranscriptional level often occurs through the cleavage of the target mRNA transcripts by the PIWI endonuclease (Figure 1Aii; Kim, 2019). In addition, piRNAs bind lncRNAs in a sequence-specific manner, thus releasing miRNAs from the binding sites of these lncRNAs and inducing target mRNA degradation (Figure 1Aiii; Kim, 2019).

Long non-coding RNAs (lncRNAs) range from 200 nts to over 100 kb, and they have been shown to play pivotal roles in numerous essential biological processes, including those leading to human diseases. LncRNAs can regulate gene expression at the epigenetic, transcriptional, and posttranscriptional level (Schmitz et al., 2016).

Long non-coding RNAs function as miRNA sponges. LncRNAs can adsorb targets in one or several miRNAs through their own miRNA reaction elements (MREs) at binding sites, further suppressing miRNA targeting of mRNAs and the degradation mediated by miRNAs (Figure 1Bi). Sponging miRNAs is among of the common posttranscriptional regulatory mechanisms of lncRNAs (Hombach and Kretz, 2016). For instance, BACE1-AS functions as a miR-761 sponge, actively suppressing the degradation mediated by miR-761 and upregulating BACE1 expression in individuals with AD (Zeng et al., 2019).

Additionally, lncRNAs function as miRNA precursors. In addition to exerting complex effects on gene expression and signal transduction, lncRNAs might also function as precursors or scaffolds for miRNAs. In this case, lncRNAs might generate specific miRNAs through intracellular RNA splicing and enhance the posttranscriptional regulation of target mRNAs (Figure 1Bii; Lekka and Hall, 2018).

Emerging studies have recently shown that miRNAs influence lncRNA function, and several lncRNAs have been shown to be regulated by miRNAs. In addition to other RNA binding protein complexes, such as the RNA-induced silencing complex (RISC), miRNAs interact with lncRNAs to regulate lncRNA stability and expression (Figure 1Biii; Lekka and Hall, 2018).

Recently, circular RNAs (circRNAs) have been shown to mediate several regulatory functions in various diseases. The circRNA-miRNA/circRNA-mRNA pathways play important roles in regulating the pathological process of AD (Akhter, 2018).

CircRNAs constitute a class of novel RNA molecules with a special covalent loop but no 5′ cap or 3′ tail, which are formed from precursor mRNAs by back-splicing and exon skipping (Granados-Riveron and Aquino-Jarquin, 2016). Among the four circRNAs biogenic mechanisms, intron-pairing-driven circularization is particularly important for circularization. ALU elements or flanking inverted repeats form circRNAs by intron pairing, and ecircRNAs or EIciRNAs are formed as introns are removed or retained, indicating that ALU elements play an important roles in intron-pairing-driven circularization (Zhang X.O. et al., 2014; Liu et al., 2020). However, ALU elements are absent in mice, and they usually rely on SINE elements to promote the formation of circRNAs.

CircRNAs are thought to function as endogenous sponges that efficiently bind and inhibit miRNA transcription, thereby further influencing downstream mRNA expression through posttranscriptional regulation and ultimately participating in various diseases, including AD (Figure 1Ci; Akhter, 2018; Qu et al., 2018). For example, circ_0000950 sponges miR-103 to increase the expression of PTGS2 and further increase inflammatory cytokine levels (Yang H. et al., 2019). In addition, circRNAs have consistently been shown to regulate gene expression levels. CircRNAs might interact with the Pol II complex in the nucleus or directly bind to RNA-binding proteins (RBPs) or RNA-associated proteins in the cytoplasm to form RNA-protein complexes that modulate mRNA transcription (Figure 1Cii). Furthermore, circRNAs were also confirmed to modulate gene expression trans-functionally by competing with the pre-mRNA splicing machinery. CircRNAs function as ‘mRNA traps’ to sequester the translation start site or disrupt the integrity of a mature linear RNA to produce a fragmented untranslated RNA or an inactive protein, thereby reducing the expression of the target protein (Figure 1Ciii; Qu et al., 2018).

MicroRNAs are involved in the proliferation and apoptosis of neurons by regulating downstream target genes or signaling pathways involved in the pathological process of AD (Figure 2).

Notably, miR-206 has been shown to decrease the expression of brain-derived neurotrophic factor (BDNF) by targeting the 3′-UTR of the BDNF mRNA and inhibiting its expression. BDNF is known to play a neuroprotective role against in apoptosis and to promote neuron survival, the formation of new synapses, and plasticity (Beeri and Sonnen, 2016; Lima Giacobbo et al., 2019). Tian et al. (2014) reported increased levels of miR-206 in the hippocampal tissue, cerebrospinal fluid, and plasma of APP/PS1 transgenic mice, indicating that it may contribute to neuronal apoptosis. The level of BDNF is reduced in individuals with many neurodegenerative diseases (Somkuwar et al., 2016; Rosa et al., 2019). In cultured neurons, BDNF protects against Aβ_1–42 toxicity (Arancibia et al., 2008). Reduced levels of BDNF in subjects with AD have also been associated with increased pro-inflammatory cytokine activity, altered oxidative stress levels, mitochondrial dysfunction, downregulation of hippocampal neurogenesis, and GSK3β hyperactivity (Liu et al., 2015). In a study by Tian et al., miR-206 targeted the 3′-UTR of the BDNF mRNA and decreased the BDNF level in AD transgenic mouse neurons, inducing their apoptosis. Li et al. showed that miR-613 targets the 3′-UTR of the BDNF mRNA and inhibits BDNF expression, thus potentially contributing to the development of AD. The findings reported by Li et al. revealed markedly increased levels of miR-613 in the serum and cerebral spinal fluid (CSF) of patients with mild cognitive impairment (MCI) and dementia of the Alzheimer’s type (DAT), as well as in the hippocampus of APP/PS1 transgenic mice (Li et al., 2016). Moreover, the increased expression of miR-613 accompanied a significant decrease in the levels of the BDNF mRNA and protein.

According to Yang Q. et al. (2019), miR-133b might play a neuroprotective role by targeting epidermal growth factor receptor (EGFR). EGFR, a member of the ErbB family, has been reported to activate the MAPK/ERK and PI3K/AKT signaling pathways, which play crucial roles in cell survival, plasticity, and protecting neurons from neurotoxicity (Bruban et al., 2015; Liu L. et al., 2019). Recent evidence implicates this receptor in neurometabolic disorders, such as AD and aging. As shown in the study by Yang et al., the serum levels of miR-133b were substantially decreased in patients with AD and positively correlated with the MMSE score. However, increased miR-133b levels attenuated Aβ-induced neuronal apoptosis by binding to the 3′-UTR of the EGFR mRNA.

Based on accumulating evidence, some miRNAs that play important roles in cell proliferation are also associated with AD to some extent (Figure 2). Important roles for miR-222 in regulating neuron proliferation have been identified, and it might contribute to the pathogenesis and development of AD (Wang et al., 2015). Moreover, miR-222 was reported to be a direct target of p27^Kip1 and was associated with cell cycle progression and proliferation (Wang et al., 2015). As shown in the study by Wang et al., miR-222 is downregulated in APPswe/PSΔE9 mice, correlating with the extent of increase in the level of the p27^Kip1 protein. Importantly, p27^Kip1 is a direct target of miR-222. Its expression inhibits the phosphorylation of pRb and arrests cell proliferation in G1 phase, thereby contributing to the pathogenesis of AD.

Thus, these miRNAs may be helpful for exploring new treatment strategies for AD by regulating apoptosis or cell proliferation signaling pathways.

Oxidative stress has been recognized as a contributing factor in aging and in the progression of AD (Wang X. et al., 2014). Oxidative stress is caused by mitochondrial dysfunction and increased production of reactive oxygen species (ROS). The increase in ROS levels affects the expression and processing of AβPP, initiating Aβ accumulation and the activation of various signaling pathways in brain tissue, further contributing to the development of AD (Yuan et al., 2018; Figure 2).

The expression of miR-98 is reduced with increased levels of hairy and enhancer of split (Hes)-related with YRPW motif protein 2 (HEY2) in AD mice, and this effect is associated with the activation of oxidative stress and mitochondrial dysfunction (Chen et al., 2019). HEY2, a transcription factor for Notch, is expressed at higher levels in individuals with some diseases. Notch signaling is closely related to the differentiation, proliferation, apoptosis and oxidative stress of several cell types (Wu et al., 2016; Bai et al., 2017; Yuan et al., 2019). The expression of miR-98 suppresses the production of Aβ and ameliorates oxidative stress and mitochondrial dysfunction by targeting and inhibiting HEY2 to inactivate the Notch signaling pathway in AD mice (Chen et al., 2019).

Another miRNA that is downregulated in the neurons of AD mice is miR-330. VAV1, a target of miR-330, is upregulated in AD mice (Zhou et al., 2018). VAV1, a conserved member of the Rho family of GTPases, functions as a crucial regulator of several neurological diseases (Garcia et al., 2012; Fry et al., 2014). Upregulation of miR-330 reduces VAV1 expression and simultaneously reduces the levels of ERK1, JNK1, P38 MAPK, and Aβ. The MAPK signaling pathway plays a crucial role in the uptake and accumulation of Aβ via the α7 nicotinic acetylcholine receptor in individuals with AD (Yang et al., 2014). As shown in a study by Zhou et al., the overexpression of miR-330 contributes to reductions in the Aβ level, oxidative stress and mitochondrial dysfunction by decreasing the level of VAV1 and activation of the MAPK signaling pathway (Zhou et al., 2018).

The autophagy process is the major cellular degradation pathway for long-lived proteins and organelles. Autophagy in neurons is essential for the maintenance of neuronal homeostasis, and autophagy dysfunction might contribute to the development of AD (Salminen et al., 2013; Li et al., 2017). The expression and function of specific ncRNAs are closely associated with autophagy in subjects with AD (Figure 2).

For instance, miR-214-3p is a functional miRNA that inhibits autophagy and apoptosis in hippocampal neurons by targeting the 3′-UTR of the Atg12 mRNA (Zhang et al., 2016). Atg12 plays a crucial role in the early step of autophagosome formation (Tanida, 2011; Romanov et al., 2012). Zhang et al. revealed reduced miR-214-3p levels in the cerebrospinal fluid of patients with sporadic AD and in hippocampal neurons from SAMP8 mice upon the induction of autophagy. Overexpression of miR-214-3p in primary neurons increases their viability and inhibits their apoptosis and autophagy by negatively regulating Atg12 expression (Zhang et al., 2016).

Neuroinflammation exerts important effects on cognitive functions in the pathophysiological processes of AD. In individuals with AD, the aggregation of Aβ results in the chronic activation of primed microglia, increasing the production of inflammatory cytokines and chemokines, which induces neuroinflammation (Marttinen et al., 2018; Figure 2). Based on accumulating evidence, several ncRNAs might regulate the intracellular pathways of numerous mediators of neuroinflammation.

For instance, miR-132 and miR-212 are associated with neuroinflammation in subjects with AD. Hadar et al. revealed the upregulation of miR-132 and miR-212 in lymphoblastoid cells (LCLs) from patients with AD, and correspondingly, the expression of silent information regulator 1 (sirtuin1, SIRT1) is decreased (Hadar et al., 2018). SIRT1 was previously verified to play a vital role in preventing the apoptotic death of neurons by regulating p53 and peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α), which decrease the accumulation of Aβ and attenuate mitochondrial dysfunction (Wang et al., 2013). Recently, mice overexpressing SIRT1 exhibited ameliorated clinical symptoms of autoimmune encephalomyelitis and attenuated axonal injury (Martin et al., 2015). SIRT1 is a target of miR-132 and miR-212, and its expression is inhibited in LCLs from patients with AD. In addition, Liu D. et al. (2019) observed increased expression of miR-155 in the hippocampus of AD rats, accompanied by increasing levels of proinflammatory cytokines. The silencing of miR-155 decreases caspase-3 levels and suppresses the inflammatory signaling pathways, ameliorating learning impairments in AD rats. Guedes et al. also identified SOCS-1 as a target of miR-155, and its expression is decreased upon miR-155 upregulation in 3 × Tg AD mice. The expression of miR-155 contributes to the production of inflammatory mediators, such as IL-6 and IFN-b, in microglia and astrocytes (Guedes et al., 2014).

Abnormalities in Aβ production and metabolism are the main causes of amyloid plaque deposition in the brain. In the brain, amyloid precursor proteins are usually subjected to posttranslational proteolytic processing by different secretases, including α-, β-, and γ-secretase. α-Secretase generates soluble amyloid protein, while β- and γ-secretases produce the β-amyloid precursor protein (βAPP), generating the amyloidogenic peptide Aβ (De Strooper et al., 2010). Dysfunction of these secretase enzymes induces abnormal Aβ deposition in the brains of patients with AD. Recently, several ncRNAs have been shown to be involved in Aβ pathology by regulating the enzymes that process Aβ.

Numerous miRNAs have been shown to regulate the expression of the APP mRNA in human cells in vitro. APP is a single-pass transmembrane protein expressed in many tissues. APP is implicated in synapse formation and the plasticity of neural tissues (Turner et al., 2003; Wang S. et al., 2016). Several miRNAs have been shown to influence APP biosynthesis, thus generating Aβ plaques. These miRNAs, including miR-101, miR-101a-3p, miR-346, and miR-384, were reported to be downregulated in animal models (Figure 2). Liu et al. reported decreased expression of miR-384 along with increasing levels of APP in the CSF of patients with dementia of the Alzheimer’s type (DAT). However, overexpression of miR-384 suppresses the expression of the APP and BACE1 mRNAs and proteins by binding the 3′-UTRs of their mRNAs (Liu et al., 2014b). The binding of miR-101 and miR-101a-3p to the 3′-UTR of the APP mRNA was confirmed, which reduced the level of APP in subjects with AD (Long and Lahiri, 2011b; Lin et al., 2019; Barbato et al., 2020). Long et al. observed a significant decrease in miR-346 expression in patients with AD, particularly patients presenting with later Braak stages. Importantly, miR-346 specifically targets the 5′-UTR of the APP mRNA to increase APP translation and Aβ production (Long et al., 2019). The suppressive effects of the miRNAs on APP expression may provide a new direction for targeted therapy for AD.

MicroRNAs involved in Aβ production induced by abnormal apolipoprotein E (ApoE) expression and functions, which contributes to AD pathogenesis (Figure 2). ApoE, the major component of high-density lipoprotein (HDL)-like particles, is required for the transfer of cholesterol and phospholipids between cells (Pamir et al., 2016). ApoE is a major risk factor for AD, particularly in patients with LOAD, and the lipid metabolism regulated by ApoE in the brain might play a critical role in AD pathogenesis (Schmechel et al., 1993).

For example, miR-1908 was shown to directly interact with the 3′-UTR of the ApoE mRNA and subsequently reduced the levels of the ApoE mRNA and protein (Wang Z. et al., 2018). Wang et al. observed increased miR-1908 levels in patients with AD, and this increase was negatively correlated with the plasma ApoE level. Therefore, miR-1908 expression inhibits ApoE expression and suppresses apoE-mediated Aβ clearance.

The upregulation of miR-33 has been observed in the brains of AD mice, effectively suppressing ATP-binding cassette transporter A1 (ABCA1) expression by binding to the 3′-UTR of the ABCA1 mRNA in neural cells (Kim et al., 2015). ABCA1 is a key regulator of ApoE lipidation, which is required for the effective clearance of Aβ from neurons. Overexpression of miR-33 impairs cellular cholesterol efflux and dramatically increases extracellular Aβ levels by promoting Aβ secretion and impairing Aβ clearance from neurons. Genetic deletion of miR-33 markedly upregulates ABCA1 levels, further decreasing Aβ secretion by inhibiting the β-site cleavage of APP and promoting Aβ clearance from neurons. Thus, miR-33 may represent a potential therapeutic target for AD by regulating the metabolism of ApoE and Aβ (Kim et al., 2015).

Recently, insulin signaling was shown to be involved in regulating neural plasticity and memory processing by protecting neurons from oxidative stress and apoptosis, which were determined to play crucial roles in the brains of patients with AD (Chen et al., 2016). Deregulation of insulin, insulin receptor, insulin-like growth factor (IGF-1), and other components of the insulin signaling pathway in the brain leads to memory impairment, tau hyperphosphorylation, and Aβ accumulation (Stohr et al., 2013; Chatterjee et al., 2019; Figure 2). Moreover, the effects of miRNAs on the insulin signaling pathway and insulin resistance has recently attracted attention (Chen et al., 2016).

According to a previous study, miR-200b/c might contribute to reducing Aβ secretion and alleviating cognitive impairment by promoting insulin signaling in the AD brain (Higaki et al., 2018). The levels of both miR-200b and miR-200c are increased in primary murine neuronal cells (PMNCs) stimulated with Aβ_1–42. Notably, miR-200b/c suppresses S6K1 expression at the posttranscriptional level and reduces Aβ-induced insulin resistance. S6K1 negatively regulates the PI3K/mTOR pathway by phosphorylating serine residues in insulin receptor substrate 1 (IRS1), leading to insulin resistance (Tremblay et al., 2007). AD mice overexpressing miR-200b/c showed decreased generation of Aβ and a greater ability to memorize the spatial location upon the amelioration of insulin resistance. Thus, miR-200b/c protects against Aβ-induced toxicity.

The upregulation of miR-26b has been observed in the temporal cortex of humans with AD, a condition associated with reduced levels of IGF-1 protein and increased Aβ production (Liu et al., 2016). The reduction in the level of IGF-1 associated with an accelerated accumulation of Aβ is a feature of the AD brain. IGF-1 plays an important role in the clearance of Aβ from the brain by mediating insulin/IGF-1 signaling. The astrocyte-derived IGF1 acts as a transporter, which can transport the intracellular toxic Aβ oligomers to extracellular in the form of endocytic processing (Pitt et al., 2017). The downregulation of miR-26b in neurons increases the level of the IGF-1 protein and suppressed Aβ production.

Tau is a microtubule-associated protein that is normally located in neuronal axons and associated with the cytoskeleton and the stabilization of microtubules. The abnormal expression and aggregation of hyperphosphorylated tau leads to the formation of neurofibrillary tangles (NFTs), which are a common pathological feature of AD (Li et al., 2007).

Several studies have described the direct regulation of tau expression by miRNAs (Figure 2). Smith et al. revealed decreased expression of the miRNA cluster miR-132/212 in individuals with AD (Hernandez-Rapp et al., 2016). Their subsequent study identified tau as a direct target of miR-132, and a miR-132/212 deficiency in mice led to increased tau expression, phosphorylation and aggregation. However, the overexpression of miR-132 in 3 × Tg AD mice induces a significant reduction in tau phosphorylation and attenuates long-term memory deficits. Another study reported a decrease in miR-219-related regulation of tau expression in subjects with AD. Importantly, miR-219 directly targets the 3′-UTR of tau to alter the expression of the tau mRNA at the posttranscriptional level (Santa-Maria et al., 2015).

Other miRNAs have been reported to play roles in modulating tau phosphorylation and subsequent tangle formation (Figure 2). For example, miR-146a, miR-322, and miR-125b are upregulated, and miR-512 and miR-137 are downregulated in the brains of patients with AD and mouse models, changes that are associated with the tau phosphorylation status. According to Wang et al., the increased expression of miR-146a might contribute to abnormal tau hyperphosphorylation in the brains of patients with AD (Wang G. et al., 2016). The rho-associated coiled-coil-containing protein kinase 1 (ROCK1) gene is a target of miR-146a in neural cells, and overexpression of miR-146a induces tau hyperphosphorylation by inhibiting ROCK1. ROCK1 has been shown to promote tau dephosphorylation by binding and phosphorylating the phosphatase and tensin homolog (PTEN) protein (Hu et al., 2019). Thus, the inhibition of miR-146a in a mouse model of AD reduces tau hyperphosphorylation and enhances memory function by regulating the ROCK1-PTEN signaling pathway (Wang G. et al., 2016). Recently, miR-322 expression was shown to be significantly increased, along with a decrease in BDNF expression in the AD mouse brain. BDNF plays a crucial role in regulating synaptic plasticity and neuronal survival and was reported to be significantly decreased in AD brains. BDNF-TrkB receptor activation is negatively regulated by miR-322 because it targets BDNF, thereby promoting tau phosphorylation (Zhang et al., 2018a). A significant increase in miR-125b expression was reported in patients with AD compared to healthy controls and was associated with the induction of tau phosphorylation (Banzhaf-Strathmann et al., 2014; Ma et al., 2017). The overexpression of miR-125b causes tau hyperphosphorylation by increasing the levels of P35, Cdk5, and p44/42-MAPK (Banzhaf-Strathmann et al., 2014). In addition, miR-125b may regulate AD and neuron growth and apoptosis by modulating the levels of inflammatory factors and oxidative stress through sphingosine kinase 1 (SphK1) (Jin et al., 2018). SphK1 is a key enzyme that regulates ceramide/sphingosine-1-phosphate (S1P), which mediates reactive oxygen species (ROS) production and plays a protective role in neurodegenerative diseases (Lin et al., 2016; Motyl and Strosznajder, 2018). As shown in the study by Jin et al., miR-125b directly targets SphK1 to suppress the level of the SphK1 protein, enhance oxidative stress, and increase levels of the amyloid precursor protein (APP), β-site APP cleaving enzyme 1 (BACE1) and tau proteins (Jin et al., 2018). Therefore, if SphK1 is overexpressed upon miR-125b silencing, learning and memory are enhanced and Aβ deposition is reduced in subjects with AD.

In addition, the levels of several miRNAs, including miR-512 and miR-137, are significantly reduced in the AD brain and accompanied by an abundance of hyperphosphorylated tau (Figure 2). As shown in a study by Mezache et al., the reduction in miR-512 expression and the increase in the expression of 2 of its antiapoptosis-related targets, cFLIP and MCL1, are associated with tau hyperphosphorylation in AD brains (Mezache et al., 2015). Jiang et al. revealed reduced expression of miR-137 along with increased expression of the calcium voltage-gated channel subunit alpha-1 C (CACNA1C) protein in the hippocampus and cerebral cortex of AD mice. Notably, miR-137 inhibited the phosphorylation of tau (p-tau) induced by Aβ₄₂ in SH-SY5Y cells by directly binding to the 3′-UTR of the CACNA1C mRNA and suppressing the expression of its protein (Jiang et al., 2018). Moreover, miR-326 also inhibits tau phosphorylation and enhances the cognitive function of mice with AD. The expression of miR-326 negatively regulates the expression of VAV1 by binding to the 3′-UTR of the VAV1 mRNA and inhibiting the activation of the JNK signaling pathway to enhance cell viability and suppress neuronal apoptosis (He et al., 2020).

Synaptic loss-induced memory impairments are an early pathological feature of AD and are thought to be induced by the accumulation of Aβ peptides. Aβ weakens synaptic transmission and disrupts long-term potentiation (LTP) (Mucke and Selkoe, 2012; Tanaka et al., 2019). Roles for miRNAs in controlling the expression of genes related to synaptic transmission, plasticity, and cognition, which are involved in the pathology of AD, have been reported (Figure 2).

Wang X. et al. (2018) reported a marked increase in the level of miR-124 in the temporal cortex and hippocampus of patients with AD and in the hippocampus of Tg2576 mice. The dramatic reduction in levels of the tyrosine protein phosphatase non-receptor type 1 (PTPN1) protein in the AD brain and a significant negative correlation between PTPN1 and miR-124 were observed in the temporal cortex. Wang et al. also found that miR-124 directly targets the 3′-UTR of the PTPN1 mRNA, an important tyrosine phosphatase, to suppress its translation, thereby impairing the function of AMPA-type glutamate receptors (AMPARs) and disrupting synaptic transmission, plasticity, and memory. The overexpression of miR-124 suppresses the expression of PTPN1, which dramatically induces synaptic impairments and memory deficits.

Baby et al. (2020) described the association of miR-134-5p expression with impaired synaptic plasticity in individuals with AD. The level of miR-134-5p was dramatically increased in the Aβ_1–42-treated hippocampus. In this study, miR-134-5p directly targeted cAMP-response-element binding protein (CREB-1) and posttranscriptionally downregulated the expression of CREB-1 and BDNF in individuals with AD (Baby et al., 2020). CREB-1 and BDNF are two of the most important plasticity-related proteins (PRPs) that mediate functional and structural plasticity (Caracciolo et al., 2018). BDNF transcription is activated by the phosphorylation of CREB following Ca²⁺ influx in postsynaptic neurons and results in CREB binding to CRE in the BDNF gene (Tao et al., 1998; Esvald et al., 2020). Knockdown of miR-134-5p increases the levels of the CREB-1 protein and CREB phosphorylation, eventually resulting in an increase in BDNF gene transcription and the rescue of the Aβ_1–42-induced impairment in synaptic function in the hippocampus of AD rats (Baby et al., 2020).

Another miRNA that directly targets BDNF is miR-10a, and it acts as a mediator of synaptic plasticity by inhibiting the BDNF-TrkB signaling pathway. Wu et al. (2018) revealed increased miR-10a levels and decreased BDNF, CREB, p38, PSD95, and TrκB expression in AD rats.

Sun et al. documented the upregulation of miR-342-5p in APP/PS1 mice that mechanistically leads to impaired synaptic function. Overexpression of miR-342-5p downregulates the expression of ankyrin G (AnkG), a protein that is known to play a critical role in the axon initial segment (Sun et al., 2014). Direct binding of miR-342-5p to the 3′-UTR of the AnkG mRNA decreases AnkG levels through repressed translation in neurons from AD transgenic mice.

Lee et al. (2016) identified a role for miR-188-5p in promoting the neurogenesis and synaptic functions of neurons, and its expression is reduced in brain tissues from patients with AD and 5XFAD mice. Furthermore, neuropilin-2 (Nrp-2), a target of miR-188-5p, is upregulated in brain tissues from patients with AD and 5XFAD mice. Nrp-2, together with its ligand semaphorin-3F, was previously reported to function as a negative regulator of spine development and synaptic structure (Tran et al., 2009). However, the expression of miR-188-5p reversed the Aβ-mediated reduction in dendritic spine density and basal synaptic transmission in 5XFAD mice by targeting the 3′-UTR of the Nrp-2 mRNA and subsequently reducing the level of the Nrp-2 protein.

Shi et al. observed a significant increase in miR-34c levels in the serum of patients with MCI and in the hippocampus of SAMP8 mice; this ncRNA plays critical roles in decreasing synaptic function in individuals with AD. Increased miR-34c expression was mediated by the ROS-JNK-p53 pathway and negatively regulated synaptotagmin 1 (SYT1) expression by targeting the 3′-UTR of the Syt1 mRNA in subjects with AD, and inhibition of miR-34c improves the memory deficits in an AD model (Shi et al., 2020).

Taken together with the aforementioned studies, the dysregulation of specific miRNAs contributes to the pathogenesis of AD by inducing synaptic dysfunction and cognitive deficits.

Recently, specific dysregulated piRNAs have been reported to be associated with the function of AD-related biological pathways, playing important roles in apoptosis and oxidative stress and in regulating Aβ levels in individuals with AD (Figure 2). Roy et al. observed increased piR-38240 and piR-34393 levels in brains of patients with AD, and these ncRNAs were purported to affect AD pathways (Roy et al., 2017). Furthermore, piR-34393 and piR-38240 both contain potential binding sites for the cytochrome C somatic (CYCS) 3′-UTR. These results confirmed the low expression of CYCS and high expression of the targeting ncRNAs piR-38240 and piR-34393 in individuals with AD. In addition, KPNA6 was reported to be another target of piR-38240. Karyopherin α6, which is encoded by the KPNA6 gene, plays an important role in maintaining cellular homeostasis during oxidative stress (Sun et al., 2011). A low level of KPNA6 expression was correlated with a high level of piR-38240 expression in that study, indicating that piR-38240 contributed to oxidative stress in individuals with AD.

The lncRNA EBF3-AS is a critical lncRNA involved in AD (Magistri et al., 2015). According to Magistri et al. (2015), the expression of the lncRNA EBF3-AS was upregulated in the brains of patients with late-onset Alzheimer’s disease (LOAD). The lncRNA EBF3-AS is transcribed from the opposite strand of the protein-coding gene early B cell factor 3 (EBF3). EBF3, a DNA-binding transcription factor, was reported to inhibit cell proliferation and to lead to cell cycle arrest, growth suppression, and apoptosis (Zhang et al., 2018b). Recently, Gu et al. revealed that EBF3-AS promoted neuronal apoptosis in subjects with AD and was involved in regulating EBF3 expression. Gu et al. observed increased levels of EBF3-AS and EBF3 in the hippocampus of APP/PS1 AD model mice. EBF3-AS knockdown reversed the changes in EBF3 expression and inhibited Aβ-induced apoptosis in SH-SY5Y cells (Gu et al., 2018).

Parenti et al. (2007) observed high expression of NAT-Rad18, the natural antisense transcript of Rad18, in the cerebellum, brainstem and cortex of AD rats. Rad18 is a member of the Rad6 epistasis group that plays an essential role in repairing DNA lesions. Furthermore, Parenti et al. observed the upregulation of NAT-Rad18 and downregulation of Rad18 in rat cortical neurons treated with Aβ_1–40.

In addition, some clinical drugs protect against neuronal injury by regulating specific lncRNAs. For example, simvastatin ameliorates memory deficits and inflammation in clinical and mouse models of AD by suppressing the expression of the lncRNA n336694. Huang et al. revealed marked decreases in the expression of the lncRNA n336694 and miR-106b in brain tissues from APP/PS1 mice treated with simvastatin (Huang W. et al., 2017). The lncRNA n336694 targets the 3′-UTR of miR-106b and increase its expression. In addition, miR-106b induces the expression of p53, Bax, caspase-3 and caspase-9 in SH-SY5Y cells, which were shown to be markers of apoptosis. Simvastatin ameliorates memory deficits and reduces Aβ plaque formation in APP/PS1 mice by suppressing the expression of the lncRNA n336694 and miR-106b (Huang W. et al., 2017).

The lncRNA SOX21-AS1 plays a key role in oxidative stress-induced neuronal injury in AD mice. As revealed in the study by Zhang et al., the expression of SOX21-AS1, which is the antisense sequence that targets FZD3/5 and regulates the Wnt pathway, is substantially increased in the hippocampal neurons of AD mice (Zhang et al., 2019). Downregulated SOX21-AS1 may potentially increase the expression of FZD3/5 by activating the Wnt signaling pathway, ultimately contributing to the alleviation of hippocampal neuronal oxidative stress, reducing the apoptosis rate and enhancing the learning and memory abilities of mice with AD.

Recently, the lncRNA activation by transforming growth factor-β (lncRNA-ATB) was reported to be involved in AD pathophysiology. Wang et al. discovered increased expression of lncRNA-ATB in the CSF and serum of patients with AD. An Aβ treatment induces PC12 cell cytotoxicity, oxidative stress, and apoptosis and increases the expression of lncRNA-ATB (Wang J. et al., 2018). Suppression of lncRNA-ATB expression alleviates Aβ-induced oxidative stress-induced injury in PC12 cells, possibly by upregulating miR-200.

The lncRNA maternally expressed gene 3 (MEG3) was suggested to be involved in inhibiting oxidative stress and inflammatory injury in subjects with AD. The level of MEG3 is decreased in the tissues of AD rats. MEG3 was identified as a tumor suppressor that inhibits both the p53-dependent and p53-independent pathways (Yi et al., 2019). According to Yi et al., MEG3 expression inhibits the activation of the PI3/Akt signaling pathway in the hippocampal tissues of AD rats. The upregulation of MEG3 contributes to decreased amyloid plaque deposition, the inhibition of oxidative stress and inflammatory injury and the amelioration of the cognitive impairment in AD rats (Yi et al., 2019).

The lncRNA 17A regulates autophagy and apoptosis in an AD cell model. Massone et al. (2011) observed increased expression of lncRNA 17A in cerebral tissues derived from patients with AD, and this lncRNA participated in mediating Aβ secretion. Furthermore, Wang et al. (2019) showed that lncRNA 17A regulated autophagy and apoptosis by targeting GABAB receptor 2 (GABABR2), whose expression is significantly increased in SH-SY5Y cells following treatment with Aβ_1–42. GABABR2 has been reported to play a role in regulating microglial function and neuroinflammation (Xu et al., 2018). Upregulated GABABR2 expression inhibits the release of proinflammatory cytokines. The expression of lncRNA 17A decreases the level of the GABABR2 protein; however, silencing lncRNA 17A induces GABABR 2 expression, suppresses cell apoptosis, promotes autophagy, and reduces the ratio of secreted Aβ_1–42/Aβ_1–40 (Wang et al., 2019).

Sortilin-related receptor 1 (SORL1) is a risk gene for late-onset AD (Xue et al., 2014). A reduction in SORL1 expression promotes an increase in neurotoxic Aβ formation in the brains of individuals with AD, indicating that SORL1 plays an important role in preventing AD progression. SORL1 interacts with APP and functions as a sorting receptor for APP. Downregulation of SORL1 expression shifts APP to the β-secretase cleavage pathway, increasing secreted APPα (sAPPβ) production and promoting Aβ formation (Khvotchev and Sudhof, 2004). Recently, the lncRNA 51A was found to be an antisense configuration of intron 1 in the SORL1 gene that drives the splicing shift of SORL1. The expression of lncRNA 51A is significantly increased in the brains of patients with AD, and it might be involved in Aβ generation in individuals with AD by inhibiting SORL1 expression (Ciarlo et al., 2013; Figure 2).

Neuroblastoma differentiation marker 29 (NDM29) is an RNA polymerase III-transcribed ncRNA, and overexpression of NDM29 might induce APP synthesis and increase β-secretase cleavage, leading to an increase in Aβ secretion that would favor the onset of neurodegenerative processes (Massone et al., 2012; Figure 2). Moreover, Massone et al. also revealed that NDM29 is unequivocally upregulated in the cerebral cortices of patients with AD, possibly contributing to the increase in Aβ secretion.

Low-density lipoprotein receptor-related protein 1 (LRP1) functions in several physiological processes, including the cellular transport of cholesterol, endocytosis of ligands, and transcytosis across the blood-brain barrier (Zlokovic et al., 2010). Recently, LRP1 has been implicated in the clearance of Aβ, and its expression is reduced in individuals with AD (Van Gool et al., 2019; Figure 2). LRP1-AS is a conserved antisense lncRNA transcribed from the LRP1 locus. Yamanaka et al. showed increased expression of LRP1-AS and decreased LRP1 expression in the brains of patients with AD (Yamanaka et al., 2015). Moreover, LRP1-AS negatively regulates LRP1 expression by binding to Hmgb2 and inhibiting the Hmgb2-mediated increase in the transcriptional activity of Srebp1à toward LRP1, indicating that LRP1-AS plays a major role in negatively regulating the systemic clearance of Aβ during AD progression.

Typically, circRNAs function as miRNA sponges in mammalian cells and have been implicated in the regulation of neuronal diseases, cardiovascular diseases and cancers (Shang et al., 2019). Recently, important regulatory roles were identified for some circRNAs in the oxidative stress pathway, and these circRNAs were potentially useful as therapeutic targets for drugs in the treatment of AD (Figure 2). For example, Huang et al. observed increased expression of mmu_circRNA_013636 (best transcript: Trpc6, chr9: 8634046-8,658,377) and decreased expression of mmu_circRNA_012180 (best transcript: Phkb, chr8: 88420328-88,446,141) in the hippocampal tissues of SAMP8 mice; however, a Panax Notoginseng Saponin (PNS) treatment reversed the changes in the expression of these circRNAs in the brains of AD model mice (Huang et al., 2018b). Their previous study shown that PNS could prevent oxidative stress injury via increasing the gene expressions and activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in the brains of SAMP8 (Huang J.L. et al., 2017). Based on these results, the mechanism regulating mmu_circRNA_013636 and mmu_circRNA_012180 expressions may be associated with the therapeutic effect of PNS on AD, and may be closely related to regulator role in oxidative stress.

Other studies revealed potential roles for circRNAs in autophagosome assembly or vesicular transport-mediated pathways (Figure 2). Huang et al. documented a significant decrease in the expression of mmu_circRNA_017963 (best transcript: Tbc1d30, chr10) in 10-month-old SAMP8 mice compared with the controls, indicating that mmu_circRNA_017963 might play an important regulatory role in AD pathogenesis (Huang et al., 2018a). Furthermore, mmu_miR_7033-3p potentially displayed the greatest interaction with mmu_circRNA_017963, which showed a high probability of participating in the biological processes of autophagosome assembly, exocytosis and the synaptic vesicle cycle, functions proven to be associated with AD pathogenesis.