Cellular and Molecular Biology
Open Access

The Telomere-to-telomere (T2T) Consortium contains a complete 3.055 billion base pair (bp) sequence of a human genome called T2TCHM13, which includes gapless assemblies for all chromosomes except Y. To date, T2T-CHM13 is the newest and most complete sequence and was published in “Science” in 2022. However, T2T-ChM13 still does not represent the entire human genome. It was reported that 63,494 of the presently annotated human genes and 233,615 transcripts. Among them, 19,969 genes (86,245 transcripts) were predicted to be proteincoding genes, while the rest consisted of introns, regulatory sequences, noncoding RNAs, and unknown and uncertain protein-coding genes [1]. There are many noncoding sequences, including various ncRNAs, introns and other sequences. In recent decades, protein-coding mRNAs and microRNAs have been widely studied, while reports about lncRNAs are still relatively rare.

In recent years, increasing evidence has proven the significant roles of lncRNAs in cellular processes and various diseases, such as cancer, the cardiovascular system rheumatoid arthritis ischemia and Alzheimer’s Disease (AD) [2-10]. For instance, the lncRNA XIST is upregulated in colon cancer tissues and cell lines, and its knockdown can inhibit tumor growth. Further study investigated whether the lncRNA X-inactive Specific Transcript (XIST) promotes colon cancer tumor growth by targeting miR-34a and the Wnt/β-catenin pathway [11]. Exosomal lncRNA Psoriasis Susceptibility-related RNA Gene Induced by Stress (PRINS) in peripheral blood serum in Monoclonal Gammopathy of Undetermined Significance (MGUS) patients has potential as a biomarker with a sensitivity and specificity of 84.9% and 83.3%, respectively, when compared to that in healthy donors [12]. Lnc- SOX6-1 expression was elevated in pediatric Acute Myeloid Leukemia (AML) patients and in various AML cells. This finding correlates with the outcomes of treatments and a worse risk of stratification [13]. The lncRNA SNHG20 has also been shown to play a vital role in Epithelial Ovarian Cancer (EOC) since it is highly expressed in EOC tissues of patients, and its knockdown can inhibit EOC cell proliferation, migration and invasion. Therefore, the lncRNA Small Nucleolar RNA Host Gene 20 (SNHG20) has potential as a diagnostic marker and treatment target [14].

lncRNA-HOTAIR affects ovarian cancer susceptibility in an Iranian population [15]. lncRNA H19 in the Iranian population was reported to be an important factor that increases the risk of breast cancer [16].

lncRNA MEG3 is a tumor suppressor. It was reported to be a predictive and prognostic marker for patients with breast cancer, while lncRNA-NEF has been found to be involved in intrahepatic cholangiocarcinoma (IHCC), a liver cancer, as a tumor suppressor [17]. Intrahepatic Cholangiocarcinoma (IHCC) patients with high plasma levels of lncRNA-Neighboring Enhancer of FoxA2 (NEF) had significantly better survival conditions than IHCC patients with low plasma levels [18]. The lncRNAs TINCR and CARLo-7 participate in bladder cancer and play a critical role in mediating bladder cancer through the Wnt/β- catenin and JAK2/STAT3 signaling pathways [19,20].

Noncoding RNAs (ncRNAs) are a class of genes that do not encode proteins. ncRNAs longer than 200 nucleotides (nt) are called long noncoding RNAs (lncRNAs), while ncRNAs shorter than 200 nt are known as small or short ncRNAs. Noncoding RNAs reported in the literature are classified as lncRNAs, microRNAs (miRNAs), transfer RNAs (tRNAs), ribosomal RNAs (rRNAs), small nuclear RNAs (snRNAs), piwi-associated RNAs (piRNAs), endogenous short-interfering RNAs (siRNAs) and circular RNAs (circRNAs) [10]. However, the type and number of human ncRNAs currently annotated by the HUGO Gene Nomenclature Committee (HGNC, www.genenames.org) are long noncoding RNAs (4514), microRNAs (1914), transfer RNAs (587), small nuclear RNAs (568), ribosomal RNAs (60), small nuclear RNAs (50), small NF90 (IRF3) (50)-associated RNAs, Y RNAs (4) and vault RNAs (4). The HUGO is the only group with the authority to approve symbols for human genes. Long noncoding RNAs consist of most noncoding RNAs [21]. miRNAs have been widely studied as a group of small ncRNAs. In contrast, scientific research on lncRNAs is emerging. Here, we focused mainly on the recent emerging roles of lncRNAs in Alzheimer’s disease.

Long noncoding RNAs (lncRNAs)

lncRNAs are a group of highly heterogeneous regulatory ncRNAs lacking a significant open reading frame. More than 50,000 lncRNAs are estimated to exist in the human genome. The majority of lncRNAs have a similar but different structure than mRNAs. In terms of similarity, they have a similar biological origin and are also transcribed by RNA polymerase II, 5-capped, spliced and polyadenylated. The difference is that lncRNAs are shorter and have fewer weakly encoded but longer exons, typically lower expression and poor conservation of primary sequences [22]. Another distinguishing characteristic of lncRNAs is strong tissue-specific expression patterns. Brain tissues are more conservative in the expression of lncRNAs than other tissues, and it is estimated that approximately 40% of lncRNAs are expressed specifically in brain tissues. Hence, lncRNAs are potentially involved in many important physiological processes in the nervous system, such as neuronal differentiation, neurite outgrowth, synaptogenesis and synaptic plasticity [23,24]. lncRNAs include linear lncRNAs and circular RNAs (circRNAs). Some studies have investigated circular long noncoding RNAs that also play vital roles in AD, such as ciRS-7, ciRS-7, circNF1-419, circHDAC9, circ_0000950 and circAβ [25].

lncRNAs have been implicated in the pathogenesis of several neurodegenerative diseases, including Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis and Huntington’s diseases [26-31]. For example, the lncRNA NONMMUG014387 promotes Schwann Cells (SCs) after peripheral nerve injury [32]. The lncRNA GAS5 affects neuron death and neuronal function in ischemic stroke. The apoptosis of neurons can be inhibited, and neuronal injury can be improved by inhibiting DNMT3B-dependent MAP4K4 methylation when lncRNA GAS5 is silenced [33]. Additionally, lncRNA SPRY4 was found to be dysregulated in Non-small Cell Lung Cancer (NSCLC) cells. NSCLC patients with low levels of lncRNA SPRY4 Intronic Transcript 1 (SPRY4- IT1) might have relatively shorter survival times. Hence, lncRNA SPRY4 also has biomarker potential [34]. In addition, lncRNA MEG3 was also found to be involved in nerve injury and injured nerve regeneration in rats with sciatic nerve defects through regulating the proliferation and migration of SCs [35]. A comprehensive profile of lncRNAs in a transgenic mouse model of Alzheimer’s disease was generated, and a total of 4622 lncRNAs were analyzed. Among them, 205 lncRNAs were significantly different. MAPT-AS1, a lncRNA, may play an important role in breast cancer [36].

The lncRNA linc00657 was found to induce neuropathic pain by mediating the miR-136/ZEB1 axis in a rat model. The reduction in linc00657 can inhibit neuroinflammation in CCI rats by targeting the expression of cyclooxygenase-2, tumor necrosis factor-α and interleukin-1β, and these outcomes were reversed by miR-136 inhibitors [37]. lncRNA embryonic stem cells expressed 1 (Lncenc1) is also a lncRNA involved in neuropathic pain. Lncenc1 interacts with EZH2 and downregulates BAI1 gene expression to affect neuropathic pain in mouse microglia [38]. Recently, downregulation of lncRNA ZEB1-AS1 was found in peripheral blood mononuclear cells of Sporadic amyotrophic lateral sclerosis (SALS) patients. ZEB1-AS1 was implicated in the pathology of neuronal differentiation [39]. Here, we emphasize linear long noncoding RNAs involved in AD.

Alzheimer’s disease

Alzheimer’s Disease (AD) is the most common neurodegenerative disease characterized by progressive memory loss and cognitive impairment. It is a disease that threatens human health worldwide. However, research into the mechanisms of AD is lagging far behind expectations [40]. Although the exact causes of the disease are not understood, it is believed that the main pathological features of AD are the dysregulation of two proteins in brain tissue, extracellular protein amyloid β (Aβ) deposition and intracellular type 2 microtubuleassociated protein (tau) aggregation or insoluble Neurofibrillary Tangle (NFT) formation [41]. The plaques caused by Aβ aggregation play a major role in cognitive decline and cell death by disrupting cellular communication and causing microglial activation and inflammation [42]. In addition to Aβ deposition, dysregulation of the protein tau also leads to AD. Hyperphosphorylated tau protein aggregates to form NFTs, which block synaptic transmission and are thought to be closely linked to cognitive decline in AD [43].

While Aβ plaques and NFTs in neurons are key features of AD, neuroinflammation has emerged as another major cause. In the pathogenesis of AD, aggregates of Aβ and NFTs trigger an inflammatory response in the nervous system, termed neuroinflammation, mediated by central Nervous System (CNS) resident glial cells such as microglia and astrocytes, inflammasomes, and inflammatory mediators including cytokines, chemokines and reactive oxygen species. Conversely, neuroinflammation leads to the deterioration of Aβ plaques and tau hyperphosphorylation, which further potentiate AD progression and contribute to AD pathology [44-46].

Many studies have shown that neuroinflammation and oxidative stress are inextricably linked and lead to most neurodegenerative pathologies, including Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease and Parkinson’s disease. Inflammatory cells secrete excess oxygen free radicals, leading to oxidative stress, and some Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS) can further promote intracellular signaling cascades to increase the secretion of proinflammatory factors, ultimately leading to neuroinflammation. Thus, neuroinflammation and oxidative stress can be mutually stimulating, especially in the disease state [47].

Dementia is diagnosed by core clinical criteria, including the appearance of interference with the ability to work or function; decline from previous levels of functioning and performing; not explained by delirium or major psychiatric disorder; and cognitive impairment is detected and diagnosed, which is related to impaired abilities in daily activities. The possible AD dementia diagnosis meets the cognitive deficits for AD, and etiologically mixed presentation meets all AD dementia clinical criteria. Currently, well-known biomarkers for judging the pathological process of AD are Aβ Positron Emission Tomography (PET) of the brain, the Aβ42/Aβ40 ratio in Cerebrospinal Fluid (CSF), low Cerebrospinal Fluid (CSF) Aβ42, increased CFS tau, including total and phosphorylated tau, and decreased Fluorodeoxy Glucose (FDG) uptake on PET in the brain [48].

For the diagnosis of AD, cognitive testing is the most common way to check for AD symptoms. If the cognitive test has difficulty determining the disease, Magnetic Resonance Imaging (MRI) and other tests mentioned above will be performed. However, there are some disadvantages. For instance, PET and MRI are not easy to widely use due to their high cost. Additionally, CSF collection requires an invasive lumbar puncture procedure with general anesthetics. It causes side effects of headache [49]. Therefore, investigating other biomarkers in blood, such as the plasma Aβ42/Aβ40 ratio, tau and Neurofilament Light (NFL), has become a topic of interest in recent years. The aims for biomarkers such as other proteins, miRNAs, metabolites and exosomes have been reported [50]. In this mini-review, we mainly summarize the comprehensive role of various lncRNAs involved in AD, including Aβ deposition, tau protein hyperphosphorylation and neuroinflammationrelated pathological processes, such as microglia and astrocyte activation, the NLRP3 inflammasome and oxidative stress.

lncRNAs as potential biomarkers or therapeutic targets in Alzheimer’s Disease (AD)

lncRNAs have been investigated to have great potential as diagnostic biomarkers and therapeutic targets in AD. lncRNAs might be a new focus for AD biomarker studies, which are critical for earlystage screening and timely prevention of AD. One of the most studied lncRNAs is BACE1-AS. The expression level of lncRNA BACE1-AS in whole plasma samples was lower in pre-AD subgroup patients and higher in full-AD patients than in healthy people. Additionally, the level of lncRNA BACE1-AS in plasma can accurately reflect pre-AD, full-AD and healthy people with good sensitivity and specificity [30,51].

lncRNA 51A in plasma, an antisense transcript of the SORL1 gene SORL1-AS (51A), has been implicated as a potential biomarker. The expression of lncRNA 51A can cause aggregation in AD patients in both the brain and plasma. The plasma 51A level has a negative correlation with Mini-Mental State Examination (MMSE) scores in AD patients [52,53]. The results from a study enrolled 120 AD patients, 120 Parkinson’s Disease (PD) patients and 120 controls and showed that lncRNA MALAT1 and its target are potential biomarkers for AD management involving FOXQ1, PTGS2 and CDK5 [54]. The lncRNA EBF3-AS promotes neuronal apoptosis in AD model mice and affects EBF3 expression, indicating that EBF3-AS has the potential as a new therapeutic target for the treatment of AD [55].

lncRNA NEAT1, reported to be a novel target for Alzheimer’s disease progression via the miR-124/BACE1 axis as mentioned above, can Mediate Microtubule (MT) stabilization by the FZD3/GSK3β/ptau pathway in SH-SY5Y cells and APP/PS1 mice. Specifically, lncRNA NEAT1 mediates the phosphorylation of tau protein through FZD3 [54,56].

lncRNAs involved in Aβ plaque formation

Aβ plays a critical role in the pathophysiology of AD by causing the death of neurons due to its insoluble and neurotoxic characteristics. Aβ usually has two isoforms, Aβ40 and Aβ42, which are generally released from amyloid precursor protein (APP) by β-secretase 1 (BACE1) and γ-secretase. The Aβ42 peptide is more toxic and has faster growth of Aβ42 aggregates. The expression of BACE1 was upregulated in the brain enzymes of patients with AD [57]. It should be noted that BACE1 transcripts are upregulated by the lncRNA BACE1-AS, which is transcribed from the opposite strand of the BACE1 gene and shares complementary sequences, and its expression is mediated in brain and vascular homeostasis [30]. In other words, lncRNA BACE1-AS expression could increase BACE1 mRNA, which in turn increases the production of Aβ [58]. Therefore, lncRNABACE1-AS plays an important role in Aplaque formation.

In addition, lncRNA X-inactive Specific Transcript (XIST) is a functional lncRNA. Yue et al., found that lncRNA XIST expression was upregulated in vivo and in vitro in AD models. The molecular mechanism of lncRNA XIST in AD models showed that silencing of lncRNA XIST downregulated Aβ protein-related BACE1 through miR- 124/BACE1 signaling pathways [59]. Similarly, lncRNA MAGI2-AS3 has been acknowledged as an important factor for Aβ deposition. Studies have shown direct interactions between MAGI2-AS3 and miR-374b- 5p and between BACE1 and miR-374b-5p. Specifically, when SH-SY5Y and BV2 cells were stimulated with Aβ25-35, MAGI2-AS3 expression increased, while miR-374b-5p expression decreased. Reduction of MAGI2-AS3 and overexpression of miR-374b-5p can cause the same effect: enhancement of neuronal survival and impairment of neuroinflammation in AD cell models. These effects can be reversed by inhibiting miR-374b-5p. Furthermore, in AD patients, MAGI2-AS3 and miR-374b-5p blood levels were also negatively correlated. lncRNA MAGI2-AS3 can interact with miR-374b-5p, indicating its critical role in attenuating neurotoxicity and neuroinflammation [60]. On the other hand, lncRNAs 17A, 51A, and NDM29 were reported to increase Aβ formation and/or the Aβx-42/Aβx-40 ratio directly or indirectly, although they may play other roles [61].

lncRNAs involved in tau hyperphosphorylation

AD is also characterized by the hyperphosphorylation of tau protein or Neurofibrillary Tangles (NFTs) in cells. Activated kinases add phosphate groups to tau proteins, which leads to their hyperphosphorylation and NFT formation [62]. These steps are regulated by multiple kinases, primarily Glycogen Synthase Kinase 3 (GSK3β) and Cyclin-Dependent Kinase 5 (CDK5) [63]. lncRNAs, such as the lncRNAs linc-00507, RP11-543N12.1 and SOX21-AS1, participate in tau hyperphosphorylation. The level of linc00507 was significantly increased in both animal and cell models of AD. Linc00507 sponges miR-181c-5p to regulate the Microtubule-associated Protein Tau (MAPT) or Tau-Tubulin Kinase-1 (TTBK1) pathway, which activates the P25/P35/GSK3β signaling pathway. Consequently, linc-00507 mediates tau protein hyperphosphorylation [64].

lncRNAs RP11-543N12.1 and SOX21-AS1 are highly expressed in SH-SY5Y cells following Aβ25-35 treatment and act as a lncRNA/ miRNA axis to promote phosphorylation of tau protein and cell apoptosis during AD progression. lncRNA RP11543N12.1 inhibits proliferation and enhances apoptosis by targeting miR3243p, indicating that RP11543N12.1 and miR3243p may be potential biomarkers and therapeutic targets in AD. lncRNA SOX21-AS1 has been found to sponge miR-107 in SH-SY5Y and SK-N-SH cells. The upregulation of tau protein phosphorylation and apoptosis and the viability decrease can be inhibited by miR-107 in Aβ1-42-treated SH-SY5Y cells. However, lncRNA SOX21-AS1 can reverse this effect of miR-107 [65,66]. The lncRNA NEAT1, reported to be a novel target for Alzheimer’s disease progression via the miR-124/BACE1 axis above, can mediate Microtubule (MT) stabilization by the FZD3/GSK3β/p-tau pathway in SH-SY5Y cells and APP/PS1 mice [54, 56].

lncRNAs involved in Microglia (MG) and astrocyte activation

Neuroinflammation is largely mediated by glial cells, including microglia and astrocytes. Activated microglia and astrocytes have been implicated as key players in the progression of AD [67]. Microglia are the major immune cells of the CNS. In response to stimuli, microglia are activated into two phenotypes, M1 and M2. The M1 type is a neurotoxic phenotype, secreting pro-inflammatory cytokines (TNF-α, IL-16, etc.) and chemokines (CCL2, IL-18, etc.) that promote neuroinflammation and induce neuronal damage and oxidative stress, thereby triggering synaptic loss and accelerating the disease process, the M2 type is a neuroprotective phenotype, releasing arginase 1, IGF-1 and Fzd1, which are involved in neuroprotection and tissue repair. Astrocytes are the most abundant glial cells in the brain, and similar to microglia, which have two phenotypes, neurotoxic and neuroprotective activation states (A1/A2), astrocytes in Alzheimer’s disease have both protective and inflammatory effects on neurons [68].

Some lncRNAs have been found to regulate AD progression by modulating the ratio of neurotoxic and neuroprotective activation states of microglia and astrocytes. The expression of lncRNA MALAT1 was significantly reduced in AD cells, animal models and human AD brain tissues. This occurred possibly through interacting with miRNAs miRs-200a, -26a and -26b, which are generally increased in AD [69]. In addition, lncRNA MALAT1 was dysregulated in Acute Spinal Cord Injury (ASCI) rat models, and its knockdown reduced ASCI possibly through inhibiting the inflammatory response of microglia [70].

Likewise, in AD rats, the expression of lncRNA MEG3 was downregulated. Conversely, upregulation of the lncRNA MEG3 improved cognitive impairment and neuronal damage and prevented astrocyte activation in hippocampal tissues in AD rats by impeding the PI3K/Akt signaling pathway [71]. In addition, several lncRNAs XIST and NEAT1 act as sponges of miR-124, which is specifically expressed in microglia, and switch microglia to an anti-inflammatory state by imbalancing the M1/M2 ratio in CNS macrophages, so these lncRNAs may also be involved in the activation states of microglia [10]. The lncRNA LEF1-AS1 can attenuate apoptosis and improve the viability of LPS-treated Spinal Cord Injury (SCI) microglia, while the lncRNA SNHG14 promotes microglial activation by regulating miR-145-5p/ PLA2G4A in cerebral infarction in a Middle Cerebral Artery Occlusion (MCAO) mouse model and microglia [72,73]. Similarly, lncRNA SNHG5 can promote astrocyte and microglial viability [74]. In addition, LPS-induced microglial neurotoxicity can be decreased by silencing lncRNA nostrill [75]. lncRNA-Cox2 induced from astrocyte-derived Extracellular Vesicles (EVs) involves the impairment of microglial phagocytic activity in mice.

Importantly, lncRNA-11496 was found to contribute to microglial apoptosis in chronic T. gondii-infected mice by targeting Mef2c, which is related to neuronal differentiation, survival, and synapse formation, by binding to Histone Deacetylase 2 (HDAC2) [76]. On the other hand, lncRNA-11496 positively regulated the expression of its target. The overexpression of lncRNA uc.80 improves depression in rats by promoting M2 polarization of microglia [77]. These findings indicate that lncRNA- might be used as a therapeutic target for treating T. gondii-induced mental and behavioral disorders in the brain. Further study on the mechanism is needed. The increase in lincRNACox2 expression led to a reduction in microglial phagocytic activity, which was restored by inhibiting the expression of lincRNA-Cox2 via siRNA interference [78]. LincRNA-EPS can reduce Cerebral Ischemia Reperfusion (CIR) injury, inflammation and oxidative stress by maintaining High Temperature Requirement Factor A1 Htra1 stability through recruiting HNRNPL [79]. lncRNA AK148321 also reduces neuroinflammation in LPS-stimulated BV2 microglia via the miR- 1199-5p/HSA5 axis [80].

lncRNAs involved in the NLRP3 inflammasome

The formation of inflammation is a key aspect of inflammatory responses. Nucleotide-binding Oligomerization domain-like Receptor containing Pyrin Domain 3 (NLRP3) is one of the most studied inflammasomes and is present in microglia and astrocytes in the CNS. Studies have shown that the NLRP3 inflammasome plays an important role in neurodegenerative diseases, particularly Alzheimer’s disease. The NLRP3 inflammasome is a multiprotein complex containing NLRP3, ASC and procaspase-1. Activation of the NLRP3 inflammasome leads to the release of caspase-1, which mediates the production of the proinflammatory cytokines IL-1β and IL-18 and induces several downstream inflammatory factors, thereby initiating inflammatory responses. These inflammatory mediators are closely linked to Aβ deposition and tau aggregation, contributing to the pathogenesis of AD [81].

The lncRNA SNHG14 expression is higher in the cytoplasm than in the nucleus of astrocytes, suggesting that the lncRNA SNHG14 may downregulate gene expression by sponging specific miRNAs.

Bioinformatics analysis predicted a binding site between miR-223-3p and SNHG14 as well as between miR-223-3p and NLRP3. The direct interactions between miR-223-3p and SNHG14, as well as miR-223-3p and NLRP34, were further confirmed by using a luciferase reporter assay. Altogether, it could be concluded that SNHG14 might sponge miR-223- 3p and thus regulate NLRP3 expression at the posttranscriptional level in the AD study [82].

The lncRNA NONRATT004344.2 is a lncRNA that is highly expressed in the brain and is also known as lncRNA 4344. Researchers found that lncRNA 4344 regulates the activated NLRP3 inflammasome in microglia, which contributes to brain function decline and neurodegenerative diseases. The results of the animal experiments showed that lncRNA 4344 sponges miR-138-5p to upregulate the expression of the inflammasome NLRP3. Conclusively, the lncRNA-4344/miR-138-5p/ NLRP3 axis plays an essential role in regulating neuroinflammation and cognitive decline by acting as a sponge of miR-138-5p to downregulate NLRP3 expression [83].

lncRNAsinvolved in oxidative stress

Oxidative stress plays an important role in the pathogenesis of AD. Oxidants and oxidative products can regulate APP and the associated secretase. This increases the expression of APP, leading to the aggregation of Aβ. In turn, irreversibly deposited Aβ disrupts the activity of N-Methyl-D-Aspartate NMDA receptors to promote the production of oxygen free radicals and excessive calcium influx into neurons, thereby inducing neuronal damage. Oxidative stress also directly interacts with the tau protein kinases GSK-3 and CDK5 to promote their hyperphosphorylation. Similar to Aβ protein, free p-tau protein aggregates to form NTFs, leading to significant oxidative stress and neurological impairment [84].

In Aβ25-35-stimulated PC12 cells, silencing of lncRNA H19 and BDNF-AS resulted in significantly increased Superoxide Dismutase (SOD) and Catalase (CAT) expression and decreased Malondialdehyde (MDA) expression, leading to a reversal of the Aβ25-35-induced oxidative stress response, suggesting that lncRNA H19 and BDNF-AS may be involved in AD development and progression via oxidative stress [85]. lncRNA SOX21-AS1 plays an important role in tau hyperphosphorylation and cell apoptosis during AD progression. In another study, scientists also found that silencing the lncRNA SOX21- AS1 alleviated oxidative stress and inhibited apoptosis in hippocampal neurons of AD mice by upregulating FZD3/5 via the Wnt signaling pathway. In other words, the lncRNA SOX21-AS1 can also regulate oxidative stress to participate in cell cycle distribution and apoptosis during AD pathology [86].

Other long noncoding RNAs involved in AD

There are many other very important lncRNAs involved in AD, but their specific biological roles and mechanisms still need to be further investigated. The expression of the long noncoding RNA MALAT1 was previously found to inhibit Cyclic AMP Response Element-binding Protein (CREB) dephosphorylation, a transcription factor that regulates cell proliferation, by PP2A. Furthermore, lower levels of MALAT1 were measured in the CSF of AD patients than in the CSF of control patients. In addition, dysregulated MALAT1 was also found in neurodegenerative and neuro-oncological disorders, indicating an important role of lncRNA MALAT1 in neurodegenerative diseases, including AD [87]. A lncRNA activated by TGF-beta, called lncRNA-ATB, was elevated in the CSF and serum of patients with AD. Prohibiting lncRNA-ATB can protect PC12 cells from neurotoxicity induced by Aβ25-35 through regulating the miR-200/ZNF217 axis [88]. In addition, lncRNAs RP11-462G22.1 and PCA3 were also upregulated in the CSF exosomes of both PD and AD patients. Some lncRNAs, such as lncRNA BC200 and NATRad18, were discovered as early as 2007. The lncRNA BC200 found in the AD patient brain may play a critical role in maintaining long-term synaptic plasticity during AD progression by regulating local protein synthesis [89]. NAT-Rad18 expressed in rat cortical neurons was previously shown to be involved in apoptosis [90] (Figure 1).

Figure 1: LncRNAs as potential biomarkers or therapeutic targets in Alzheimer’s Disease (AD).

A systematic study on the lncRNA profile investigated a total of 14 upregulated lncRNAs and 20 downregulated lncRNAs in Peripheral Blood Mononuclear Cells (PBMCs) of AD patients compared with those in the control groups (fold change ≥ 2.0, p<0.05). Among them, lncRNAs TTC39C-AS1, lnc-AL445989.1-2, LINC01420, lnc-CSTB-1 and LOC401557 may play critical roles in AD pathogenesis. Notably, the most significant one is the antisense transcript of the TTC39CAS1 gene, which is closely related to neurogenic atrophy [91,92]. In addition, hippocampal lncRNA profiles in AD rats were reported. A total of 315 lncRNAs were found to be significantly dysregulated in the AD model rats (≥ 2.0-fold, p<0.05). The expression profiles of lncRNAs in the hippocampus of intranasal LPS-induced AD model mice were determined by microarray analysis. A total of 395 lncRNAs were differentially expressed in AD rat and mouse models compared with controls (>2.0-fold, p<0.05) [93,94].

Other lncRNAs reported in AD patients, mice, rat or cells are BDNF-AS, upregulated in peripheral blood of AD patients; ANRIL, knockdown of it reduces Aβ-induced apoptosis, inflammation and autophagy in PC12 cells; HOTAIR, downregulated in the brain by exercise in rat model; N336694, upregulated in the brain of AD model mice; PART1, increased by Aβ in endothelial cells; SNHG1, increased by A25-35 in SH-SY5Y cells; SOX2-OT, lincRNA-p21, upregulated in AD model mice; Rpph1, upregulated in the cortex of AD model mice [95-97]. There are still deregulated lncRNAs, such as TTC39C-AS1, LOC401557, CH507-513H4.4, CH507-513H4.6, CH507-513H4.3, RP11-462G22.1, and PCA3, in AD patients [52].

Over the past two decades, the role of miRNAs has been comprehensively studied. lncRNAs account for the majority of ncRNAs and have been found to be involved in various biological processes and diseases. lncRNA XIST is involved in colon cancer, lncRNA PRINS in Monoclonal Gammopathies (MGUS), lnc-SOX6-1 in Acute Myeloid Leukemia (AML), lncRNA SNHG20 in Epithelial Ovarian Cancer (EOC), lncRNA-HOTAIR in ovarian cancer, lncRNA H19, lncRNA MEG3 and lncRNA MAPT-AS1 in breast cancer, lncRNA-NEF in liver cancer, lncRNAs TINCR and lncRNAs CARLo-7 in bladder cancer, and lncRNA SPRY4 in lung cancer. There are certainly more unknown lncRNAs that contribute to cancers.

In this review, we focused on summarizing lncRNAs and their critical potential roles in key pathological features of AD, such as Aβ plaques, tau hyperphosphorylation and neuroinflammation, as well as their interactions. As described above, these lncRNAs directly or indirectly regulate vital genes or proteins that may play an important role in the development of AD. Therefore, studying these lncRNAs and their disease-related regulatory mechanisms may provide new ideas for identifying effective treatments for AD. Seventy-five percent of AD patients worldwide have not been diagnosed, mostly in underdeveloped countries. Further study on lncRNAs as biomarkers or intervention targets may provide new insights into diagnosing and treating AD.

Notably, some lncRNA studies have only been carried out in the brains of laboratory animals and or cell models, but these models have not been able to accurately recapitulate the various features of AD. Therefore, there may be significant difficulties in translating results from AD models to humans. In-depth studies investigating more lncRNAs that have essential biological roles in the development of AD and studying their mechanism are still the major topic in the future. Furthermore, research on lncRNA biomarkers and lncRNA-targeted drugs is also very important. However, the application of regulatory lncRNAs in AD still has many challenges to overcome. For example, due to insufficient research, unexpected risks and inappropriate pathological effects may occur when lncRNA-targeted drugs are used clinically. Nevertheless, we believe that with continued innovation in experimental methods and techniques, the application of safe and effective lncRNA-associated biomarkers or drugs for the treatment of AD is possible.

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