Unknotting the Role of circRNAs and IGF2BP3 in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a complex neurological ailment that is associated with memory loss, confusion, and mood disturbances. Genetic, molecular, and cellular factors, including oxidative stress, inflammation, neurotransmitter alterations, and amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs), are associated with the disease. These can be associated with protein and DNA damage, mitochondrial dysfunction, energy shortages, inflammation, and hippocampal neuron death. Circular non-coding RNAs (circRNAs) are covalently closed and essential to many physiological and pathological processes. CircRNA may be a molecular modulator of neurodegeneration, as it may influence protein transcription and interaction with essential RNA-binding proteins (RBP) in the cortical and hippocampal regions, particularly in photoreceptor neurons and white matter.Insulin-like Growth Factor 2 mRNA-Binding Protein 3. (IGF2BP3), which belongs totheinsulin-like growth factor 2 encoded mRNA-binding protein family, affects neuronal differentiation, synaptic plasticity, translation, localization, mRNA stability, and neurogenesis. Research indicates that IGF2BP3 has been reported to modulate neuron survival and function genes, as well as BACE1 translation, which creates Aβ. AD has a complex etiology; thus, understanding its molecular processes is crucial. Investigating circRNAs and IGF2BP3 activities may reveal new disease are associated with and therapy options. This review explores the emerging roles ofcircRNAs as diagnostic biomarkers and potential therapeutic targets inmanagingAD.

Introduction

ADis a progressive, most common neurodegenerative mental health complication, characterized by memory loss, cognitive deficits, improper daily life activities, misplacing items, and symptoms worsen over time. Multiple pathological mechanisms contribute to the disease progression, but intracellular deposition of Aβ and extracellular formation of NFTsfrom hyperphosphorylated tau proteins are the primary pathological characteristics of AD (Scheltens et al. 2021). Along with mitochondrial dysfunction, oxidative stress generation, and neuroinflammation, neuronal apoptosis also plays a pivotal role in disease pathogenesis. As the disease worsens, patients may find solving problems, making decisions, and managing their tasks more challenging. Difficulties infacial or other expression, comprehension of spoken as well aswritten language, mood swings, and attitude (such as rage, indifference, or anxiety) are all possible side effects(Bhatia and Sharma 2024; Malarmathi et al. 2022). Its development is due to a web of interrelated genetic, molecular, and cellular processes, and a few of these harmful processes involve oxidative stress, inflammation of the nervous system, alterations in neurotransmitters, and the formation of Aβ (1–42) plaques and NFTs. Protein and DNA damage, impaired mitochondrial function, energy shortages, inflammation, and neuronal loss in the hippocampus are all possible outcomes of these processes, which might elicit symptoms similar to AD (Perluigi et al. 2024). When tau protein is hyperphosphorylated, it is associated with intracellular NFTs to develop. The neuronal cytoskeleton is disrupted by these tangles, which impairs axonal transport and eventually is associated with neuronal death. Activated microglia and astrocytes induce chronic neuroinflammation, an important step in the development of AD (Hill & Gammie 2022; Chen et al. 2023). Although the original goal was to remove Aβ and debris, ongoing inflammation worsens harm to neurons. Oxidative damage to DNA, lipids, and proteins in the brain is facilitated by an increase in reactive oxygen species (ROS) generation and a decrease in antioxidant defense mechanisms (Ismail et al. 2020). This, in turn, promotes neuronal malfunction and death, leading to the loss of synapses and poor communication between neurons, whichisassociated with tau pathology and Aβ oligomers, which interfere with synaptic function(Sciaccaluga et al. 2021).

CircRNAs represent a distinct class of molecules present throughout eukaryotic transcriptomes. These versatile regulatory elements participate in diverse biological mechanisms under both normal and disease conditions (Beylerli et al. (Beylerli, et al., 2024)). A primary regulatory mechanism involves circRNAs acting as competing endogenous RNAs that sequester microRNAs, thereby modulating target gene expression and interacting with essential RBPs. As we age, we accumulate more of the circRNAs in certain areas of the brain, including the cortex, hippocampus, white matter, and photoreceptor cells (Jiang et al. 2024). The unique way these molecules are distributed throughout the brain allows researchers to make circRNAs viable options for use in the biomarker identification process for neurodegenerative diseases such as AD. The concentrations of circumjacent RNAs have been significantly elevated in many patients suffering from AD, both in the blood and in the synaptic spaces within the brain, suggesting that these molecules may play a role in the pathogenesis and progression of these diseases (Amelimojarad & Amelimojarad 2025; Ma et al. 2020).

A covalently bonded closed-loop structure is what defines this unique type of non-coding RNA known as circRNAs. This structure is what provides them with an extremely stable and persistent presence in the cell. The way in which these molecules are created is by means of the back-splicing process of pre-mRNA (Liu et al. 2022a, b).

CircRNAs play various additional roles as gene expression modulators for a number of biological pathways after their initial roles in neural development and cognition. CircRNAs compete with other RNAs and serve as molecular decoys for miRNAs, impacting mRNA degradation and translation efficiency (Xu et al. 2021). CircRNAs can also affect RBP function by changing their subcellular localization and how they bind to target RNA. While rare in occurrence, some circRNAs are capable of coding for functionally active proteins via translation (Zang et al. 2020). The pathophysiological features comprising AD consist of altered circRNA expression profiles, with certain types leading to amyloid beta protein accumulation, hyperphosphorylated tau, and inflammation. The exceptional structural properties and numerous functions of circRNAs make them good candidates for innovative diagnostic biomarkers and treatments in managing AD (Garbuz et al. 2021; Huang et al. 2020a, b).

IGF2BP3 is a member of the IGF2- RNAbinding protein family and serves as an important post-transcriptional gene regulator (Cui et al. 2020). In addition to regulating the production of mRNA from DNA, this protein affects many other aspects of mRNA metabolism, including mRNA stability, subcellular localization, and translation of mRNA into protein (Ren et al. 2020). Neuroscience research has focused on IGF2BP3 because it plays a key role in important neurobiological functions such as neuronal maturation, synapse regulation, enhancing protein production, mRNA localization, mRNA stability, and neurogenesis (Ga et al. 2018). In addition to its role in the brain, IGF2BP3 affects many other cellular processes, including differentiation, regulation of growth, and the response to proliferation signals. Recent data suggest that IGF2BP3 may contribute to neurodegeneration through the regulation of mRNAs that code for proteins necessary for neuronal survival and normal brain function (Yang et al. 2022). IGF2BP3 appears to bind to mRNAs that encode important components of the brain, including synapse machinery and neurotrophic factors, regulating their expression levels. IGF2BP3 has also been implicated in the regulation of stress granule dynamics (cytoplasmic aggregates of ribonucleoproteins that are formed during cellular stress). Impaired formation and dissolution of stress granules may be linked to neurodegeneration, and both processes involve IGF2BP3 (Gebauer et al. 2021). Recent findings have indicated that the contribution of IGF2BP3 to the pathogenesis of AD is significant. Studies have demonstrated that IGF2BP3 is involved in the regulation of translation of BACE1, which is the β-secretase enzyme that produces Aβ. The detailed understanding of the molecular mechanisms that underlie the multifaceted etiology of AD is critical for developing targeted therapeutic approaches. CircRNAs and IGF2BP3 are emerging research areas in relation to AD and other neurodegenerative diseases. Continued investigation into the functional roles of these two molecules could provide new insight into the mechanism of action of both AD and other diseases, as well as the potential for new therapeutic targets.AD is now considered to be a worldwide health problem, yet many of the pathogenetic pathways causing this illness remain largely unknown. Therefore, elucidating the unknown aspects of AD pathophysiology will improve the efficacy of the methods used to identify and treat this condition. (Hrubešová et al. 2019)

This review seeks to elucidate the interplay between circRNAs and AD pathobiology, followed by an examination of a diagnostic tool and treatment possibilities of circRNAs in the course of the disease. Therefore, this review will be the first of its type to examine the connection between AD, IGF2BP3, and circRNAs.

Although several recent reviews have explored the roles of circRNAs in AD and the involvement of RBPs in neurodegeneration, most studies address these topics separately or within the broader context of transcriptomic regulation. Existing reviews mainly focus on the general regulatory functions of circRNAs, such as their roles as microRNA sponges, modulators of gene expression, or potential biomarkers in neurodegenerative diseases (Silva et al. 2025). Also, when reviews discuss RBPs and their role in neurological disorders, such as tauopathies and other protein aggregation-related diseases, they mainly focus on their role in RNA stabilization, splicing, and translation (Uneri et al. 2024). However, the nature of the interplay between circRNA and the RNA-binding protein IGF2BP3 has not yet been systematically described in relation to Aβ pathology in patients with AD. The possibility of a regulatory axis consisting of circRNA and IGF2BP3 may have a role in key pathogenic processes involved in AD, such as Aβ accumulation, tau hyperphosphorylation, and neuroinflammation (Patel et al. 2025). This review will summarize available evidence related to the interaction of circRNA and IGF2BP3 and its potential mechanistic relationship to AD pathogenesis and progression.

Literature Search Strategy

A comprehensive literature search was performed to identify studies investigating circRNAs, the RNA-binding protein IGF2BP3, and their potential roles in Alzheimer’s disease. Electronic databases, including PubMed, Scopus, and Web of Science, were systematically searched using combinations of the keywords “circRNA”, “circular RNA”, “IGF2BP3”, “RNA-binding proteins”, and “Alzheimer’s disease”. Studies published between 2010 and 2025 were considered for inclusion. Only peer-reviewed articles written in English and focusing on molecular mechanisms, biomarkers, or therapeutic aspects related to circRNAs and IGF2BP3 in neurodegeneration were included. Additional relevant publications were identified by manually screening the reference lists of selected articles.

The Role of circRNAs in AD

Beyond their structural characteristics, circRNAs have been increasingly implicated in AD-related molecular pathways.CircRNAs are predominantly found in several ways and exhibit a significant degree of improvement in neurons and synapses, as compared tootherdevelopmental phases of brain tissues (Tang et al. 2025). Several studies have implicated circRNAs in the pathology of AD. These circular RNAs can interact with microRNAs (miRNAs), acting as miRNA sponges, and thus regulating the expression of miRNA target genes involved in AD-related processes(Vakili et al. 2023). Providing a crucial potential biomarker to detect AD, the downregulation of hsa_circ_00033, statistically significant, offers CircHDAC9 can sponge miR-138 in vitro AD experiment to restore Sirt1 suppression and too high Aβ generation (Lu et al. 2019). CircRNAs with a neural enrichment bind with the regulatory protein, like Pur-α,to influenceAD development (Song et al. 2022). Additionally, circRNAs can also interact with RBPs, modulating their activity and affecting RNA processing, another crucial aspect of AD(Zhang et al. 2021; Zhang et al. 2020).

Even though a lot of work has been done on circRNA. They are thought to be involved in aging as well as associated with the neurodegenerative disease process, especially in AD (Kinoshitaet al. 2021). Therefore, they could play an important role in the development of AD and are considered ideal candidates for therapeutic targets, as well as for the identification of patients who may develop cognitive impairment later in life. A distinction must be made between circRNA changes that occur only due to normal aging and circRNA alterations that occur specifically due to AD progression. To this end, detailed information from microarray and/or RNA sequenced data from multiple regions of the brain, including the parietal cortex, hippocampus, FTLD, posterior cingulate, entorhinal cortex, para-hippocampal gyrus, and others in aging and age-matched healthy individuals with and without AD was used (Dube et al. 2019; Cervera-Carles et al. 2020). Studies have shown that ciRS-7 promotes protein degradation of APP and BACE1 rather than regulating their transcription. ciRS-7 does so by inhibiting NF-κB and by producing at least one cytoplasmic pool of NF-κB. Additionally, it has been found that APP dramatically reduces levels of ciRS-7. As such, these two elements are in turn influenced by one another (Shi et al. 2024a, b). Therefore, it seems that ciRS-7 is both a neuroprotectant and an important regulator in the development of AD. Remarkably, several of the circRNAs also originate from the same hosts and may impact various critical behaviours of the brain, including RTN4 or NTRK2 (Shen 2023).(Fig. 1).

Fig. 1.

CircRNAs play a role in AD development

This diagram shows how circRNAs may lead to the development of several neurological diseases, especially AD. CircRNAs play a role in AD development in several ways. CircRNAs have been reported to modulate microglial activation, a critical step in neuroinflammation. Through modulating microglial cell activity, they influence the response towards inflammatory stimuli in the brain during AD. CircRNAs also influence the formation and clearance of Aβ, a key component of amyloid plaques in AD, by regulating genes involved in Aβ synthesis and clearance, which may make them AD biomarkers. Their stability in plasma and exosomes favors them as a promising non-invasive diagnostic alternative. On the other hand, circRNAs have been reported to modulate neuronal and astrocyte autophagy, which degrades damaged cells to maintain health. Deregulation of autophagy can be associated with toxic protein buildup and contribute to AD pathogenesis. Additionally, circRNAs participate in regulating synaptic function. AD is associated with cognitive impairment due to synaptic damage. CircRNAs affect neurotransmitter transmission at synapses and plasticity genes. Primarily, mitochondrial dysfunctions and other factors mediated by oxidative stress also play a major role in the development of AD, and the circRNAs have been reported to modulate brain cell responses to it.

Regulation of Aβ Pathways

The accumulation of Aβ is a critical factor in the progression of AD.Recent research hasindicated a potential correlation between circRNAs and Aβ metabolism, which encompasses Aβ production and clearance. β-secretase 1 (BACE1) and γ-secretase sequentially cleave Aβ from the APP, and aberrant APP and BACE1 are associated with the regulation of Aβ production(Mo et al. 2020). CircRNAshave been implicated in the regulation of the expression of the APP and BACE1 genes in previous studies. For instance, it has been recently reported that circAPP, which is derived from APP, functions as a template for the synthesis of Aβ (Vakili et al. 2023; Li et al. 2020a, b). Increased expression of the gene cirCwc27 has been the result of the altered expression profile of the circRNA in AD. It appears that cirCwc27 may bind with Pur-α, thus blocking Pur-α from binding with genes that are associated with AD, as noted by Song and co-workers (Song et al. 2022). circRNA ciRS-7 may also reduce Aβ level either by inhibiting the nuclear factor-κB (NF-κB)/UCHL1 pathway or by enhancing the degradation of APP and BACE1 via the proteasomal and lysosomal pathways. CircHDAC9 may play a role in APP-mediated processing defects associated with AD via the miR-138/Sirtuin-1 pathway (Vakili et al. 2023). circAXL may also regulate the expression of the BACE1 gene by modulating its miR-328 population; therefore, these data provide supporting evidence for this. A disintegrin and metalloproteinase 10 (ADAM10) is a transmembrane metalloproteinase enzyme that mediates the non-amyloidogenic processing of APP. It has been shown in the past that circHDAC9 expression levels are lower in AD patients compared to controls. Thus, circHDAC9 can increase the expression of the ADAM10 gene in APP/PS1 transgenic mice by inhibiting the expression of miR-138, resulting in decreased levels of Aβ. Overall, these findings suggest that circRNAs are involved in the regulation of Aβ production (Lu et al. 2019).

Modulation of Tau Phosphorylation and Aggregation

Early research also examined the correlation between circRNAs and tau, a critical pathological characteristic of AD that generates NFTs under pathological conditions and results in severe cognitive impairments(Olufunmilayo et al. 2023). The subsequent discoveries are noteworthy in terms of mechanism. It has been demonstrated that tau circRNAs can be translated into proteins and that the proteins translated by tau circRNAs form aggregates similar to NFTs, promoting the formation of tau fibrils(Vakili et al. 2023). Consequently, circRNAs are responsible for the regulation of NFT production. Additional research has demonstrated that circPCCA acts as a competitive binding partner for miR-138-5p, leading to suppressed GSK-3β function and subsequent enhancement of tau phosphorylation (Wen et al. 2024). This demonstrates that circRNAshave been reported to modulate tau phosphorylation. The evidence presented above suggests that circRNAsare involved in tau aggregation (Fig. 2).

Fig. 2.

CircRNA as a possible AD treatment

Recent research indicates that circRNAs participate in the pathophysiology and progression of AD via several pathways, including metabolism of Aβ, hyperphosphorylation of tau proteins and their aggregations, oxidative stress-mediated apoptosis, mitochondrial dysfunction, and neuroinflammation.Solid arrows represent experimentally validated mechanisms in Alzheimer’s disease, whereas dashed arrows indicate inferred or indirect regulatory interactions derived from circRNA-miRNA studies.

Involvement in Synaptic Function and Plasticity

Prior analyses utilizing Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes concerning circRNAs in the brain indicated a significant association with the regulation of synaptic plasticity(Yang et al. 2024), corroborated by various in vitro and in vivostudies. As an example, the countenance of several genes and their associatedsynaptic plasticity and neuro-psychiatric disordersare believed to be influenced by a circRNA known as circHomer 1, which is derived from the precursor RNA of Homer scaffold protein 1 (Zimmerman et al. 2020). The prefrontal brain and hippocampus of rhesus macaques have been shown to have an age-dependent and male-specific elevation of CircGRIA1, a conserved circRNA isoform derived from the AMPA receptor component GRIA1. In hippocampal neurons, circGRIA1 silencing promotes synaptogenesis and counteracts age-related declines in the frequency and amplitude of spontaneous mEPSCs(Yu et al. 2023). He demonstrated that the silencing of circHIPK2 augmented the differentiation of neural stem cells into neurons and facilitated neuronal plasticity in vitro by altering synaptic formation, hence aiding the expedited recovery of ischemic brain tissue post-stroke. Nrf2, a neuroprotective drug, can enhance circ-Vps41 expression, hence increasing the quantity of synaptic vesicles and dendritic spines in the hippocampus, which improves memory deficits(Amini et al. 2024;Zhang et al. 2022a, b). All of these studies indicate that circRNAs have a role in the regulation of neuronal plasticity. These investigations further show that circRNAs contribute to cognition under normal physiological conditions, with significant variation in the circRNAs engaged in distinct memory functions. Further research is required to elucidate the principal circRNAs implicated in the distinct processes of memory, such as fear memory and spatial memory, along with their probable mechanisms (Xu et al. 2025).

CircRNAsand Neuronal Autophagy

CircRNAs are a unique class of non-coding RNA that are unmatched by other non-coding RNA classes. CircRNAs differ from all other forms of non-coding RNA in that they do not have terminal modifications such as a 5’ cap or 3’ poly-adenylated tail because of the nature of their circular, covalently linked structures (Qin et al. 2020). The circular structure of circRNA has cardioprotective effects due to the circular nature of circRNA, which makes circRNA more stable inside cells, making it less susceptible to degradation by endogenous ribonucleases. Recent studies have shown that circRNA can act as regulatory molecules through various functional mechanisms, such as transcriptional regulators, regulating intracellular signalling pathways, and regulating pathological processes associated with neurodegenerative diseases (Dorostgou et al. 2022).Neuronal autophagy, which is the engulfment of cellular components into large cytoplasmic compartments termed autophagosomes in which subsequent degradation occurs, is one of the new areas of research with the circRNAs. Autophagy is a very specific process by which cells break down and reuse damaged or unnecessary pieces that make up a cell’s interior, such as proteins and organelles (Li et al. 2021a, b). Recent research has started to investigate how circRNAs affect autophagy in neurons, which is a key function of cellular quality that may influence what happens when cellular components are encased within double membrane vesicles called autophagosomes for degradation by lysosomes. Thus, autophagy is a catabolic pathway that permits a cell to remove damaged proteins and organelles and use their components again (Li et al. 2024a, b, c).The precise regulation of this degradative system is essential for neuronal survival, as these post-mitotic cells must continuously manage the cellular damage resulting from their intense metabolic activity (Stavoe & Holzbaur, 2019).

CircRNAs Associated with AD: Evidence-based Classification

circRNAs have been implicated in multiple processes relevant to AD pathology, including amyloid processing, tau regulation, neuroinflammation, autophagy, oxidative stress, and mitochondrial dysfunction(Smail et al. 2026). However, the level of experimental validation differs considerably across reported circRNAs. Therefore, they are categorized below based on the strength of available evidence.

Confirmed AD-Associated circRNAs

Several circRNAs have been experimentally validated as dysregulated in AD using high-throughput RNA sequencing followed by qPCR confirmation in human brain tissues and biofluids. Among the most studied examples is ciRS-7, which is significantly downregulated in the hippocampus of AD patients. This circRNA normally functions as a sponge for miR-7, and its reduction may lead to altered regulation of genes involved in amyloid processing and neuronal survival. Another circRNA, circHDAC9, has been reported to be decreased in AD brain tissue and is associated with increased Aβ production through the miR-138/SIRT1 pathway (Stavoe & Holzbaur, 2019). Additionally, altered expression of circAXL and circCwc27 has been observed in AD models and patient samples. These findings demonstrate that specific circRNAs show reproducible disease-associated expression changes, supporting their involvement in AD pathogenesis and highlighting their potential as molecular biomarkers for diagnosis and disease monitoring.

CircRNAs Implicated in Related Neurodegeneration Models

In models of neurodegeneration (e.g., PD and stroke), some circRNAs have been shown to have potential regulatory effects on neuronal injury and neurodegeneration. For instance, in ischemic stroke, circDLGAP4 has been demonstrated to have neuroprotective properties through the modulation of the miR-143 pathway, and this leads to decreased neuronal apoptosis and inflammation. Furthermore, circSLC8A1 was upregulated in dopaminergic neurons under oxidative stress conditions and plays a role in neuronal survival and mitochondrial function in PD. Similarly, circHIPK2 has been shown to have an association with astrocyte activation and inflammatory responses in brain injury (Ding, et al., 2022). While these circRNAs still require further validation in human AD samples, the pathways that they are involved with, i.e., oxidative stress, neuroinflammation, and apoptotic death, are significantly implicated in AD (Beylerli, et al., 2024). Together, data from other neurodegenerative models provide indirect support for the hypothesis that circRNAs may have influences on amyloid metabolism, tau phosphorylation, and neuroinflammatory signaling in AD.

Host Gene-Derived Candidates

Several circRNAs have been thought to affect AD due to connections between their host genes and neurodegeneration. Three examples include SIRT1, BDNF, and DNM1; these three genes are particularly interesting because they regulate the maintenance of SIRT1, BDNF, and recycling DNM1 of neurons, synapses, and Aβ protein production, respectively. SIRT1 has been demonstrated to have a neuroprotective effect and to regulate amyloid precursor protein processing. BDNF is essential for synaptic stability and cognition (Hosaka et al. 2023), and DNM1 is an integral part of both synaptic vesicle recycling and neuronal signaling. Therefore, circRNAs that originate from these genes may have a role in disrupting AD-related pathways (synaptic dysfunction, neuronal stress responses, protein aggregation). However, in general, circRNAs identified as candidates for AD have not been validated using various methods, including bioinformatic and RNA sequencing, and have not been characterized for the specific isoform that has a back-splice junction in the brains of individuals with AD or in biofluids. Consequently, their functional relevance in AD pathogenesis remains uncertain and should be interpreted cautiously until further experimental validation confirms their expression patterns and mechanistic roles (Table 1).

Table 1.

Role of different circRNAs in AD

circRNA ID	Species	Model	Expression (↑/↓)	Mechanism	Phenotype readout	Evidence strength	References
ciRS-7 (CDR1as)	Human	AD hippocampus	↓	miR-7 sponge	Impaired Aβ clearance	High	(Olsson et al. 2014)
mmu_circRNA_013636	Mouse	SAMP8 AD mice	↑	Not fully defined	Associated with AD progression	Medium	(Beylerli et al. 2024)
mmu_circRNA_012180	Mouse	SAMP8 AD mice	↓	Not fully defined	Associated with synaptic dysfunction	Medium	(Bao et al. 2021)
circHDAC9	Mouse	AD mice	↓	miRNA sponge	Modulates neuroinflammation and Aβ-related pathways	Medium	(Ebanks et al. 2020)
circ_0000950	Rat/Cell	Aβ1–42-treated cortical neurons & PC12 cells	↓	miRNA sponge	Increased neuronal apoptosis, inflammation	Low	(Yang et al. 2019; Abidin et al. 2023)
CircAXL	Human (cell line)	Aβ1–42-treated SK-N-SH cells	↑	miRNA-mediated regulation	Knockdown reduced Aβ1–42-induced cytotoxicity and apoptosis	Low	(Wang et al. 2020)
circ_0002945	Human (serum + cells)	AD serum & Aβ25–35-treated neurons	↑	ER stress modulation	Attenuated ER stress and apoptosis	Medium	(Beylerli et al., 2024)
circ_0049472	Human (cell)	Aβ-treated SK-N-SH & CHP-212 cells	↑	Not fully defined	Enhanced proliferation, reduced apoptosis	Low	(Beylerli, et al. 2024)
circ_0003611	Human (cell)	Aβ-treated SH-SY5Y/SK-N-SH cells	↑	Not fully defined	Reduced inflammation, oxidative stress, apoptosis	Low	(Li et al. 2022a, b)
circHECTD1	Mouse	tMCAO (stroke model)	↑	Autophagy regulation	Astrocyte activation	Supporting (non-AD)	(Ortiz-Rodriguez and Arevalo, 2020)
circNF1-419	Mouse	D-galactose-induced senescence model	↑	Protein interaction	Delayed aging phenotype	Supporting (non-AD)	(Diling et al. 2020)
hsa_circ_0004381	Human (cell)	MPP+-treated SK-N-SH (PD model)	↓	Not fully defined	Improved viability, reduced apoptosis	Supporting (non-AD)	(Li et al. 2021a, b)
circPTK2	Mouse (cell)	OGD-treated microglial cells	↑	miRNA sponge	Microglial activation	Supporting (non-AD ischemic)	(Yang et al. 2020a, b)
circLPAR1	Human (cell)	Aβ25–35-treated CHP-212 & IMR-32	↑	Inflammatory signalling	Increased oxidative stress and apoptosis	Low	(Bian et al. 2023)

Emerging Targets of circRNAs in AD Pathogenesis

It demonstrated their alterations across silicon scaffolds and suggested a large number of circRNAs as emergent targets for research in AD pathogenesis in recent years (Shi et al. 2024a, b). Several lines of evidence, including these findings, indicate that circRNAs may be involved in diverse pathophysiological processes leading to AD, including Aβ accumulation, tau protein aggregation, neuroinflammation, and synaptic and cellular stress responses. In one of the earliest functional studies based on the functional circRNAs, Hansen et al. revealed that the testis-specific circular RNA produced by the Sry (Sex-determining region Y) gene functions as a sponge for miR-138, potentially influencing memory and learning activities (Burgos et al. 2021). Emerging circRNAs targets for the pathogenesis of AD, based on recent study findings, include:

APP and Aβ Production Emerging Target

CircRNAs derived from the APP gene have been emerging as regulators for APP expression and its further processing to Aβ. Such circRNAs could modulate APP levels and may hence contribute to Aβ accumulation in AD(Urdánoz-Casado et al. 2023). Targeting those circRNAs may prove to decrease Aβproduction. CircAPP is a circRNA derived from the APP gene that has been reported to modulate APP expression in AD and thus could be targeted to modulate Aβ levels. Itmay be another emerging target. The findings from new studies imply that some circRNAs work as miRNA sponges and hoard them from acting as suppressors of APP expression. Although these circRNAs alter APP levels, they ultimately contribute to the development of AD by causing amyloid plaques to accumulate regularly. Additionally, those might increase the levels of action absorbed linked to lowering the production of amyloid beta. Targeting CircAPP, for example, a circRNA produced from the APP gene that may influence APP expression in AD, may aid in the manipulation of Aβ levels (He et al. 2021).

Tau Proteins and Neurofibrillary Tangles (NFTs)

CircRNAs that have been reported to modulatetau-associated genes (e.g. MAPT), which encode the tau protein; tau phosphorylation and tau aggregate formation in AD have also been implicated in such circRNAs (Rybak-Wolf & Plass, 2021). CircRNAs such as circMAPT (derived from the MAPT gene) are implicated in tau’s post-translational modifications to support tau phosphorylation. Hyperphosphorylated tau accumulates to form NFTs, and it is harmful to neurons (Rawat et al. 2022). CircMAPT and other circRNAs pertinent to tau regulation represent a potential tau-patent approach to modifying tau pathology in AD.

Inflammation and Neuroinflammation

CircRNAs that act as emerging targets in inflammation include circNF-kβ, which is known to have been reported to modulate important inflammatory pathways in AD pathogenesis. Neuroinflammation, featuring the up-regulation of microglia and subsequent release of proinflammatory cytokines is highly characteristic of AD (Cai et al. 2022). CircNF-kBhas been established to modulate the NF-kBpathway, which may influence inflammation. May suppression of circNF-kB and/or of other inflammatory-inducible circRNAs may reduce neuroinflammation and thus promote neuronal survival in AD (Liu et al. 2022a, b).

Synaptic Dysfunction and Cognitive Decline

CircRNAs regulating BDNF and Sirt1 are emerging key molecules for the psychomotor activities in AD patients on synaptic plasticity and cognitive function (Duarte-Silva et al. 2022).CircSirt1 and circBDNF reverse the expression of these genes, which are important for synaptic plasticity, learning, and memory. In AD, both reduced BDNF and Sirt1 levels are directly linked with cognitive decline. Targeting the circRNAs that directly or indirectly modulate the functions of these two genes will offer the necessary restoration activities for synaptic function and cognition in AD patients (Lauretti et al. 2021).

Autophagy and Protein Homeostasis

New Research Results Indeed, autophagy is the breakdown of misformed proteins and damaged organelles; metabolic abnormalities commonly observed in AD lead to protein aggregation. The gene ATG4-B, which is used in the autophagy process, is modulated by circAtg4B (Pan et al. 2022). Disruption of circRNA modulation in autophagy may provide a therapeutic avenue for AD by allowing clearance of such toxic proteins from the brain, such as Aβ and tau.

Oxidative Stress and Cellular Defense

CircRNAs have been reported to modulate the FoxO3 gene and are implicated in oxidative stress response during AD. Oxidative stress is one of the most important and most acknowledged contributors to neuronal injuries in AD. CircFoxo3 has been demonstrated to have been reported to modulate FoxO3 expression, involved in oxidative stress-induced apoptosis (Mormone et al. 2023; Chen et al. 2022). Targeting circFoxo3 or other circRNAs associated with pathways engaging the cellular stress response may be beneficial for neuron protection against oxidative injury, and is very significant to develop AD pathogenesis (Li et al. 2024a, b, c). In a preclinical study using the hippocampus of SAMP8 AD mice, Huang and his coworkers demonstrated that elevated levels of mmu_circRNA_0136 are involved in lowering the level of mmu_circRNA_012180, which was expected to interfere and have been reported to modulate the expression of 631 and 462 mRNAs (Wu et al. 2024).

Mitochondrial Dysfunctions

CircRNAs regulating mitochondrial genes, like circMfn2, are being further investigated for possible association with AD (Mirzaei et al. 2023). Mitochondrial defects are most commonly present in AD, leading to neuronal death. CircMfn2 acts on Mfn2, which affects mitochondrial fusion. Manipulating circMfn2 may potentially benefit mitochondrial dynamics and augment energy generation at the cell level, offering a therapeutic target for mitochondrial dysfunction in AD(Liu et al. 2021).

CircRNAs: An Epigenetic Regulator

Several circRNAs are implicated in the regulation of epigenetic mechanisms, including chromatin remodelling and gene expression modulation. CircRNAs could direct epigenetic regulators, including histone deacetylases and DNA methyltransferases, to influence gene expression in neurodegenerative disease (Li et al. 2022a, b). SeveralcircRNAs are reported to participate in epigenetic mechanisms like chromatin remodelling or gene expression modulation. They may manipulate such circRNAs to affect the reversibility of these epigenetic changes associated with AD (Paniri et al. 2024). CircRNAs could be said to directly interact with epigenetic regulators like histone deacetylases and DNA methyltransferases to may influence gene expression related to neurodegeneration.

IGF2BP3 may also interact with circRNA-mediated regulatory networks in AD. Emerging studies suggest that circRNAs can function as molecular scaffolds or regulators of RNA-binding proteins, thereby influencing mRNA stability and translation. In this context, circRNAs may modulate the activity of IGF2BP3 by affecting its binding to target transcripts involved in amyloid processing, synaptic regulation, and neuronal survival (Li et al. 2022a, b). Although direct experimental evidence in AD remains limited, the potential interaction between circRNAs and IGF2BP3 represents an important regulatory axis that may contribute to disease progression.

The Role of IGF2BP3 in AD

IGF2BP3 has received extensive attention as a potential factor in the research into and treatment of AD. The major influence of IGF2BP3 on post-transcriptional gene regulation concerns the fact that it can affect mRNAs that are important to brain homeostasis in their stability, localization, and translation processes (Deng et al. 2021).

Proposed model illustrating potential involvement of IGF2BP3 in Aβ-related pathways. Direct interaction between IGF2BP3 and apoE4 has not been conclusively demonstrated in human AD brain tissue. Solid arrows represent experimentally supported Alzheimer’s disease mechanisms, whereas dashed arrows indicate inferred regulatory relationships involving IGF2BP3 or circRNA-associated pathways.

The primary pathological features of AD, tau and Aβ, have been linked to anomalies involving neurodegeneration, synaptic dysfunction, and the buildup of pathogenic proteins. IGF2BP3 is known to regulate the stability and translation of multiple mRNA targets involved in cell signaling and stress responses. Recent studies suggest that RNA-binding proteins often function within complex regulatory networks that include non-coding RNAs such as circRNAs. In this context, circRNAs may act as molecular scaffolds or modulators of IGF2BP3-mediated mRNA regulation. Although direct evidence in AD remains limited, potential circRNA-IGF2BP3 interactions could influence AD-related pathways, including Aβ metabolism, tau phosphorylation, and neuroinflammatory signaling (Mancarella and Scotlandi, 2020). Modifying the expression of IGF2BP3 and/or its interactions with target mRNAs may offer new opportunities to slow or prevent disease progression (Fig. 3).

Fig. 3.

IGF2BP3 increases the regulation of Aβ and tau in AD via different kinase enzymes

IGF2BP3 Expression and Functions in the Brain

IGF2BP3 is generally expressed during the development of the embryo and aids in differentiation and the growth of neurons. It is not expressed abundantly in adults but is still retained in the region concerning cognition, such as the hippocampus and prefrontal cortex. Protects target mRNAs from degradation, assuring the long life of the synthesis of key proteins. Enhances or represses the translation of certain mRNAs depending on the cellular context.mRNA stability has been reported to be modulated during oxidative stress, heightened in AD (Vecchiarelli & Tremblay, 2023).

Interaction with Aβ and Tau Proteins

IGF2BP3 may appear to influence both the stability and translation of mRNAs coding proteins actively involved in the synthesis and generation of the Aβ peptides. Importantly associated with AD pathology, Aβ accumulates as plaques in the brain. The IGF2BP3 is the protein believed to influenceamyloid genesis, probably through directly interacting with mRNAs governing the processing of APP (Ramanan et al. 2020).Although IGF2BP3 has been implicated in the regulation of transcripts associated with amyloid processing, direct biochemical evidence demonstrating physical binding between IGF2BP3 and apoE4 protein in human AD brain tissue remains limited. Most available findings suggest indirect regulatory roles mediated through mRNA stability rather than confirmed protein-protein interaction (Vecchiarelli and Tremblay, 2023). Therefore, the proposed IGF2BP3-apoE4 relationship should be interpreted cautiously and regarded as a hypothetical model pending further experimental validation.Tau proteins help maintain microtubule stability, but rather become hyperphosphorylated and tangled within neurons in patients suffering from AD. Indeed, IGF2BP3 may be responsible for tau pathology as well by affecting mRNA stability and translating tau, whichmay amplify tau accumulation (Gebauer et al. 2021). The mRNAs that include a certain sequence are specifically bound to the IGF2BP3,which promotes the translation of these mRNAs. It is thought that alterations in the expression levels of key proteins that are involved in Aβ and tau aggregation might occur.

Impact on Synaptic Dysfunction and Neuronal Survival

It could affect the synaptic transmission and plasticity, which are vital for different cognitive functions, if there is a dysregulation of IGF2BP3. The interaction of IGF2BP3 with translational machinery may lead to defective synaptic protein synthesis, impairing synaptic maintenance and memory formation (Gebauer et al. 2021). The protein also interacts with several signalling pathways, which are linked to neuronal survival. Neuronal apoptosis may be promoted by dysregulation of IGF2BP3 expression during the neurodegenerative phase of AD, which may interfere with survival signals. Furthermore, neuroinflammatory responses are believed to have been reported to be modulated by IGF2BP3. Chronic neuroinflammation is a hallmark of AD, and it may even influence this process through its interaction with immune response proteins, thereby causing synapse loss and neuronal death (Shi & Huang, 2023).Evidence linking IGF2BP3 to P13K/Akt/GSK-3β signaling pathways is largely derived from non- neuronal systems and cancer models. In neural contexts, available studies mainly reported associations between altered IGF2BP3 expression and downstream kinase activity rather than direct causal activation. Perturbation-based studies remain limited (Gebauer et al. 2021). Additionally, conflicting data suggest that IGF2BP family members may exhibit context-dependent effects on kinase signaling pathways.

Variants of IGF2BP3 in AD Pathogenesis

Single-nucleotide polymorphisms in the IGF2BP3 gene may change its function and expression, leading to an increased risk of developing AD. Such genetic polymorphisms can modify their action in regulating the biosynthesis of either Aβ or tau, increasing interference with synaptic function or reducing neuronal survival potential. Variants in the IGF2BP3 may also modify subject-to-stress responses relevant to the experience of AD (Liu et al. 2023a, b), such as oxidative damage or pathological protein degradation, including Aβ removal. Such variants could increase susceptibility to developing AD or influence disease severity. Several IGF2BP3 variants may modify their interaction with RBPs or other cellular machinery regulating those genes critical to AD. This may contribute to a deregulation of critical neurodegeneration proteins (Gebauer et al. 2021). The detailed discussion on several genetic variants of IGF2BP3 and their role in AD is discussed in Table 2.

Table 2.

Genetic variants of IGF2BP3 in AD

Variant type	Genomic location	Effect on protein	Potential impact on AD pathogenesis	References
Single Nucleotide Polymorphisms (SNPs)	rs3741792	Altered Expression	Changes in IGF2BP3 expression may affect neuronal stability and synaptic function.	(Zhao et al. 2024)
Insertion/Deletion	–	Altered Binding Affinity	Insertion of extra sequences or deletions may disrupt the binding of IGF2BP3 to target mRNAs like APP or tau, influencing AD pathology.	(Gebauer et al. 2021)
Copy Number Variations (CNVs)	Chromosome 14	Gene Dosage Effects	Increased or decreased copy number may lead to an imbalance in IGF2BP3 regulation, affecting AD-related gene networks.	(Gebauer et al. 2021)
Missense Mutations	Various	Amino Acid Substitution	Mutations may affect RNA-binding capacity, potentially leading to improper mRNA regulation in AD-related genes.	( Chatterjee et al. 2021)
Splice Site Variants	–	Mis-splicing of Exons	Splicing defects may be associated with truncated or dysfunctional IGF2BP3 proteins, contributing to cognitive decline.	(Wang et al. 2022a, b)

Evidence for circRNA–IGF2BP3 Interactions

Direct Binding Evidence

Direct biochemical evidence demonstrating interactions between circRNAs and IGF2BPs has mainly been reported in non-neuronal systems, particularly in cancer models. Several experimental approaches, including CLIP-seq and RIP, have been widely used to identify RNA molecules that physically interact with RNA-binding proteins. Recent studies indicate that circRNAs can directly bind IGF2BP family members and regulate post-transcriptional gene expression through stabilization of target transcripts. For example, circRNAs can interact with IGF2BP proteins to form RNA protein complexes that enhance the stability of oncogenic mRNAs through m6A-dependent mechanisms (Liu et al. 2023a, b; Shi et al. 2024a, b). In renal cell carcinoma, the circRARS transcript was shown to bind IGF2BP3 and promote recognition of m6A-modified transcripts, thereby increasing the stability of downstream target genes and facilitating tumor progression (Liu et al. 2023a, b). Such findings demonstrate that circRNAs can directly associate with IGF2BP proteins and regulate RNA metabolism. However, despite these advances, comparable biochemical evidence demonstrating circRNA binding to IGF2BP3 in neuronal tissues remains extremely limited. Currently, no large-scale CLIP-seq datasets from AD brain tissues have systematically mapped circRNAs associated with IGF2BP3, highlighting an important knowledge gap in the field.

Functional Evidence

In addition to directly binding to m6A-modified mRNAs, circRNAs can also affect the functional activities of various RNA-binding proteins, including members of the IGF2BP family of proteins. This is evident through evidence demonstrating that circRNAs are capable of modulating gene expression using several methods, such as acting as scaffolds for the assembly of ribonucleoprotein complexes, acting as molecular decoys to sequester members of the RNA-binding protein family, or influencing the interaction between proteins and their target mRNAs. Recently, it has been shown that many circRNAs are capable of regulating mRNA stability via interactions with IGF2BP proteins, which are m6A “reader” proteins that recognize methylated RNA transcripts, as well (Shi et al. 2024a, b; Yin et al. 2025). For instance, circRNAs that interact with IGF2BP2 or IGF2BP3 may promote the stability of certain mRNAs and subsequently influence cellular signaling pathways involved in processes such as proliferation, metabolism, and inflammation (Yin et al. 2025). In cancer, circRNA-mediated recruitment of IGF2BP proteins has been shown to increase the stability of target transcripts through m6A-dependent mechanisms (Yin et al. 2025). However, in the areas of neurobiology and neurodegenerative disease, currently, there is no direct functional evidence supporting that perturbation of circRNA directly alters the IGF2BP3-dependent stabilization of AD-related transcripts. Thus, although the underlying molecular mechanisms are biologically plausible, independent experimental validation in neuronal systems is still necessary.

Evidence in AD vs. Non-AD Systems

Experimental evidence supporting circRNA-IGF2BP interactions is varied significantly depending upon the system under investigation. In cancer biology, there are a number of studies that show the interaction of circRNAs with IGF2BP proteins using biochemical assays and in vitro experiments, providing evidence that circRNAs can affect mRNA stability and translation via IGF2BP mechanisms (Liu et al. 2023a, b; Yin et al. 2025). However, studies assessing the interaction between circRNAs and IGF2BP proteins in the nervous system have been limited, even though circRNAs are both enriched in neurons and known to regulate synaptic plasticity and neuronal gene expression. Direct evidence regarding circRNA-IGF2BP interactions has been particularly limited in studies involving either post-mortem brain tissue from individuals withAD or in experimental models of AD (Liu et al. 2023a, b). Currently, no comprehensive studies have directly shown the binding of circRNAs to IGF2BP3 in AD samples taken from human brains. Thus, the majority of proposed circRNA-IGF2BP3 regulatory mechanisms that occur in AD are based on inference from cancer biology or computationally generated predictions rather than direct experimental evidence.

Although there are a number of studies looking into how circRNAs bind to RNA-binding proteins in other contexts of biology, there have been few systematic studies performed on the mechanism of action of circRNA-IGF2BP3 binding interactions specifically in AD. One reason for the variability between studies is likely due to the different experimental methodologies, analytical approaches, and disease models used in different research groups. A particularly important factor in providing a basis of comparison between studies is that there are no published large-scale RNA-protein interaction datasets from human brains with AD, thus creating a gap of knowledge regarding interactions between circRNA and IGF2BP3 on a large scale. To understand the mechanism of action of circRNA-IGF2BP3 interaction networks in AD pathophysiology, it will be necessary to utilize future transcriptome profiling and RNA-protein interaction assay technologies in AD brains.

Interplay Between circRNAs and IGF2BP3 in AD

In the context of neurodegenerative diseases, especially AD, both circRNAs and IGF2BP3 have the potential to serve as significant regulatory molecules that modulate gene and/or related protein expression. CircRNAs are circular non-coding RNAs that have closed covalent structures and are resistant to exonucleases, making them stable inside the cell. Moreover, they are highly abundant in the brain and are thought to play a role in neural homeostasis and synaptic plasticity, among others. (Xiao et al. 2024).IGF2BP3, a member of the IGF2BP family, RNA-binding protein that may have been reported to modulate the stability, translation, and localization of target mRNAs. In this context, we hypothesize that a functional interplay between circRNAs and IGF2BP3 may contribute to AD pathogenesis, potentially influencing neuroinflammation, synaptic dysfunction, and Aβ- related pathways (Uddin et al. 2022). A proposed model suggests that circRNAs might act as molecular sponges or modulators of IGF2BP3, thereby indirectly affecting the expression of AD-relevant genes.

Potential Interactions Between circRNAs and IGF2BP3

CircRNAs may act as sponges, scaffolds, or decoys to interact with IGF2BP3 in several ways. These interactions can manipulate the binding and regulation of target mRNAs by IGF2BP3, including transcripts associated with neural function and neurodegenerative processes (Huang et al. 2020a, b). CircRNA dysregulation in AD may sequester IGF2BP3 or promote its abnormal activation, thereby disrupting certain regulatory pathways. In other words, circRNAs influence whether IGF2BP3 will stabilize the mRNA of APP, a crucial protein in the synthesis of Aβ. Dysregulation caused by circRNA production may lead to the development of Aβ plaque, which is a defining characteristic of the pathology associated with AD (Zhou et al. 2023). In addition, circRNA can interfere with neurofibrillary tangles associated with tau aggregation by disrupting the association between the RNA-binding protein IGF2BP3 and tau mRNA stability and instability. In addition to the effects on mRNA stability, circRNA may also change the subcellular localization of IGF2BP3 and thus influence how it interacts with various neuronal compartments at the synapse. The circumstantial interactions of IGF2BP3 with mRNA involved in synaptic physiology could have an effect on synaptic plasticity and the release of neurotransmitters; this effect is particularly important in AD because these effects occur in conjunction with synaptic dysfunction, one of the earliest indicators of cognitive decline.

CircRNAs can also act as decoys that sequester IGF2BP3 from interacting with specific targets, allowing it to function properly. Properly stabilized or destabilized mRNAs are thought to worsen molecular dysfunctions like AD. CircRNAs can sequester IGF2BP3 away from antioxidant-encoding mRNAs in elder adults, increasing the overall oxidative stress experienced by individuals with AD (Alzarea, 2025).

Regulatory Networks: CircRNAs-Mediated Modulation of IGF2BP3 Activity

The regulatory networks built around circRNAs and IGF2BP3 are very complex, owing to feedback and feedforward loops, which may provide cell homeostasis or push towards some pathological changes in AD. Therefore, this might be a positive or negative effect, where circRNAs can alter the activity of IGF2BP3 by changing its binding affinity and specificity for target mRNAs, which consequently affects the expression of these genes important for neuronal viability and functioning (Mancarella & Scotlandi, 2020). Aberrant expression of circRNAs in AD could well lead to maladaptive regulation of IGF2BP3, thereby promoting progression of the disease. For example, circRNAs may increase or decrease the ability of IGF2BP3 to stabilize the mRNAs of pro-inflammatory cytokines and thus modulate neuroinflammatory responses. One of the primary pathological conditions directly related to AD is neuroinflammation (Zhang et al. 2022a, b), where circRNA-IGF2BP3 interactions might mediate increasing or waning intensity of neuroinflammation. A similar condition might apply to other mRNAs involving axonal transport, synaptic vesicle trafficking, or mitochondrial function (Yashooa et al. 2025).

Reciprocal regulation between circRNAs and IGF2BP3 may add one further level of complexity. Thus, while circRNAs could have an impact on the activity of IGF2BP3, they may also modify the production of circRNAs through splicing or back-splicing of precursor mRNAs. Hence, it results in a system with dynamic regulation, in which the change of one component maybe able to extend through the system to have wide-ranging changes in gene expression (Mancarella & Scotlandi, 2020).

The CircRNA-IGF2BP3 network has great potential as a therapeutic target by restoring healthy contacts or severing unhealthy ones, it may be able to mitigate some of the molecular dysfunctions underlying AD. Synthetic circRNAs, for instance, may be produced to compete with the dyshave been reported to modulated natural circRNAs and thereby restore IGF2BP3’s normal regulatory functions. IGF2BP3-targeting small compounds or interactions between this protein and particular circRNAs could open up new therapeutic avenues (Yao et al. 2022).

Biomarker Potential of circRNAs and IGF2BP3 in Alzheimer’s Disease

The insight gained from the mechanistic studies into circRNAs has led to research into the potential of circRNAs as circulating biomarkers. The inherent stability of circRNAs allows detection of circRNAs from both brain tissue and peripheral biofluids like plasma, serum, CSF, and exosomes. Changes in the profiles of circRNAs have been observed in the samples of patients with AD as well as in experimental models of AD, suggesting potential for use as both diagnostic and prognostic biomarkers. However, despite this promise, there are challenges to translating circRNAs into clinical practice. Variability in circRNA expression profiles can be attributed to differences in the processing methods of the samples, the analytical methods/tools used to analyze circRNAs, and the sample populations included in each study (Pastor-Navarro et al. 2024). In addition, most studies have utilized relatively small sample sizes, limiting the application of results to larger populations. Therefore, more extensive, multicenter studies with standardized methodologies are necessary to establish circRNAs as useful and reliable biomarkers of AD. As an RNA-binding protein that regulates mRNA stability, IGF2BP3 may also be a viable candidate to use as a complementary biomarker for AD, particularly if dysregulation of IGF2BP3 reflects post-transcriptional regulatory networks in AD.

Clinical Biomarker Readiness and Translational Considerations

Pre-analytical Variables

The development of circRNAs as reliable circulating biomarkers in AD requires strict control of pre-analytical variables. Studies of extracellular RNA (including exRNA and small non-coding RNA) indicate that circulating RNA measurements can be substantially affected by the type of blood collection tube, the time between collection and processing, centrifugation conditions, and hemolysis. Various anticoagulants and tube materials will cause cells within the tubes to lyse and release intracellular RNAs before processing, introducing an artifactual increase or decrease in the amount of target circRNA if the pre-analytical protocol is not properly standardized or reported (Pastor-Navarro et al. 2024). An example of the impact of pre-analytical variables is that an extended time for processing after collection or extended storage of samples may alter the RNA profile due to ongoing transcription and degradation of RNA from cells when samples are not processed quickly or stabilized. Additionally, the type of plasma or serum prepared may influence the level of cellular contamination and platelets, thus impacting the quality of circRNA quantification. While CSF provides higher specificity to the CNS since it is in proximity to neuronal pathology, CSF collection is invasive (Yashooa and Nabi 2022). An alternative to CSF is the isolation of neuron-derived extracellular vesicles from peripheral blood; however, their utility for enriching CNS-specific circRNAs requires the establishment of standardized, quality-controlled methodologies across laboratories.

Analytical Validation

Appropriate and thorough analytical validation of circRNAs depends on the use of targeted analytical techniques that can reliably discriminate circRNAs from their linear counterparts. PCR assays using back-splice junction-specific (BSJ) primers (to amplify only circular RNA species) and Sanger sequencing of BSJ amplicons are often used to authenticate circularity. High-throughput RNA seq techniques (with optimized enrichment strategies such as rRNA depletion and RNase R treatment) improve circRNA variant detection and quantification and allow for inter-library normalization of circRNA quantities; however, no accepted internal control has been developed for quantitative determination of circulating circRNA, making inter-sample comparisons and biomarker validation difficult (Lin et al. 2025). RNase R resistance assays can be used to assess the structural circularity of a given circRNA; however, the extent of RNase R resistance may depend upon sequence-level features of each circRNA, and certain structural linear RNAs can complicate interpretation. Inter-laboratory reproducibility, assay sensitivity, dynamic range, and normalization methodology will continue to be the primary challenges in standardising analytical workflows for circRNAs (Wang et al. 2025).

Clinical Validation and Diagnostic Performance

In order to demonstrate the clinical validation of circRNA biomarkers, independent cohorts with sufficient statistical power must undergo rigorous assessment to demonstrate reproducibility and generalizability. The ability to discriminate between disease and control groups must also be assessed using ROC curve analysis, with statistical measures to quantify discriminative ability (e.g., area under the curve, sensitivity, specificity, positive predictive value, negative predictive value). In the context of neurodegenerative diseases, demonstrating disease specificity is critical by assessing biomarkers against healthy controls and against other neurodegenerative diseases, including frontotemporal dementia and vascular dementia, to identify disease-specific changes rather than generalized neurodegenerative changes (Beylerli et al. 2024). Furthermore, there is emerging evidence that circRNA panels and machine learning models have high area under the curve and sensitivity for discriminating between disease states; however, there are still limited large prospective validation studies that are needed to validate clinical utility (Beric et al. 2024). Finally, standardized procedures surrounding sample collection, assay execution, and statistical validation are essential to translate circRNAs into clinically reliable diagnostic tests.

Confounding Factors

To ensure that alterations in the circRNA level indicate processes related to the AD disease itself rather than relating to other factors (non-specific to AD), any potential confounding factors must be controlled. One of the strongest risk factors for AD is age; therefore, older individuals (non-age-specific) will show differences in their peripheral and central molecular profiles (including RNA expression) compared with younger persons, potentially confounding the association of circRNA biomarkers if age is not adjusted for statistically. There are also sex differences that mediate the development of AD, as well as sex-specific molecular (phenotypic) differences associated with AD, which occur via sex-specific inflammatory/metabolic pathways. Thus, these differences should be accounted for in stratified analyses by sex and/or age, where applicable (Konwar et al. 2025a, b). In addition, the APOE genotype (especially the APOE E4 allele) affects the risk of developing AD as well as its interaction with other vascular burden and systemic profiles, and if not taken into account in a study, creates a confounding factor that affects the measurements of circulating biomarkers for AD (e.g., levels of C-reactive protein. Examples of other potential confounders of circRNA differences may include vascular, metabolic (systemic inflammatory condition), and vascular and systemic inflammatory comorbidities that exist in individuals, some of which may be risk factors for developing a neurodegenerative disorder and, thus, potentially lead to confounding results in the analysis of the data (Abuduwaili et al. 2024). Therefore, multivariate adjustment and a clinically stratified cohort design are required to identify specific circRNAs in the serum of individuals with AD compared with the general population.

Therapeutic Implications of circRNAs and IGF2BP3 in AD

Given their potential therapeutic value in regulating pathways implicated in AD, both circRNAs and IGF2BP3 have been proposed as therapeutic targets. CircRNAs associated with IGF2BP3 will be an important basis for understanding future advances in AD treatment as research into these biomolecules progresses; examples include end-user and/or professional uses of circRNAs and IGF2BP3 treatments. Many pathways have been identified as being involved in the development of AD, such as Aβ aggregation and tau hyperphosphorylation, chronic brain inflammation, and synaptic dysfunction, and studies have demonstrated that the dysregulation of circRNAs and IGF2BP3 activity has been found to negatively affect many of these pathways (Kumar et al. 2024). Therefore, therapeutic approaches that focus on circRNA and IGF2BP3 to develop new therapies targeting the underlying causes of AD rather than its symptoms could make significant progress in the management of this disease.Although the discovery of potential therapies presents hope in the fight against AD, there are many unknowns about how the mechanism between circRNAs and IGF2BP3 promotes the progression of AD. A lot of the data we currently have about this interaction is based on either non-neuronal experiments or computational predictions (Panchalingam et al. 2024). Therefore, additional experiments utilizing AD-derived neuronal models and samples collected from AD patients will be required to validate the mechanisms described above, as well as to determine if targeting the interactions between circRNAs and IGF2BP3 are feasible method of therapeutic intervention.Potential future directions for research and treatment of AD may arise from a robust interaction between circRNA & IGF2BP3. Both of these molecules have been implicated in the development of pathogenic processes associated with AD, which leads to AD and its progression.Targeting these two molecules and their interactions will facilitate realizing genuine disease mechanisms rather than symptom relief (Wen et al. 2024).

The interaction between circRNAs and IGF2BP3 provides an exciting area for research and therapy in AD. Dysregulation of circRNA and IGF2BP3 activities has been associated with pathogenic pathways or mechanisms regarding AD, such as Aβ aggregation, tau hyperphosphorylation, neuroinflammation, and synaptic dysfunction. Intervention in these interactions and targets could provide novel therapies that may address actual mechanisms of diseases rather than symptom relief (Nogales et al. 2022).

Targeting circRNAs as Therapeutic Strategies in AD

They are expressed predominantly in the brain and are stablecircRNAs that have become attractive candidates for therapeutic intervention. Aberrant expression levels of circRNAs in AD signify that restoring their physiological levels might reverse subsequent degeneration (Abidin et al. 2023). Therefore, pathogenic circRNAs may be targeted for degradation by anti-sense oligonucleotides or small-interfering RNAs, which selectively deprive IGF2BP3 of activity. By reducing their capacity to sequester IGF2BP3, these molecules will be able to bind to particular circRNAs and stabilize the target mRNAs that are essential for the health of neurons.

On the other hand, the synthesis of synthetic circRNAs that resemble protective endogenous circRNAs that were under-expressed in AD could be considered (Khan et al. 2022). Such engineered circRNAs may act as decoys that trap IGF2BP3 to avoid its action on stabilizing proinflammatory or proapoptotic mRNAs. For instance, such artificial circRNAs could interfere with the effects of IGF2BP3 on mRNAs encoding cytokines involved in inflammation or proteins participating in Aβ production, thus reducing neuroinflammation and plaque deposition.

Potential Role of IGF2BP3 Modulation in AD Treatment

Although its primary function is mRNA stability, IGF2BP3 also becomes dissave been reported to be modulated in cases of AD, and hence can produce an aberrant protein expression pattern. Direct modulation of IGF2BP3 activity is yet another potential avenue for therapy (Ma et al. 2024). Development of small-moleculesuppressors or activators may allow fine-tuning of the binding of IGF2BP3 to its mRNA targets. For example, some suppressors of IGF2BP3 may reduce the stabilization of APP mRNA, perhaps thereby reducing Aβ production. In contrast, enhancers of the IGF2BP3 stabilization of neuroprotective mRNAs may provide possible support for synaptic resilience and neuronal survival (Shi and Huang, 2023). Research into modulating levels of IGF2BP3 through gene-editing technologies such as CRISPR-Cas9 holds promise (Yashooa et al. 2026). Manipulating the expression upwards or downwards of IGF2BP3 may restore balance in the disrupted regulatory networks in AD, particularly in certain brain regions. Targeted, durable therapeutic effects might be gained from the delivery of these gene-editing tools to affected neurons through viral vectors.

Emerging Approaches for Combined circRNAs and IGF2BP3 Targeting

The positive impacts of circRNA and IGF2BP3 methods can work in concert. Therefore, dual-targeting ought to enable the regulation of both circRNA levels and IGF2BP3 activity, thereby repairing regulatory networks with more accuracy. As an example, certain treatments may use ASOs to break down circRNAs that are sick and small compounds to alter IGF2BP3’s affinity for particular mRNAs (Kim et al. 2024). Combined approaches could target multiple pathological processes in AD, such as neuroinflammation, synaptic dysfunction, and protein aggregation.

Nanotechnology-based delivery systems, such as liposomes or nanoparticles, may be used for co-delivery of circRNA-targeting and IGF2BP3 modulator molecules directly in the brain, without the blood-brain barrier challenge, thus targeting the affected neurons. Multi-omics and advanced bioinformatics may further facilitate identifying specific circRNA-IGF2BP3 interactions to be targeted in developing highly individualized therapies for AD patients (Al Ali et al. 2024).

Prospects for Clinical Application of circRNAs and IGF2bp3 in AD

The potential of circRNAs and IGF2BP3 to be utilized as biomarkers for diagnosis and treatment inAD is promising. These are important molecules involved in several significant pathological processes of AD that include Aβ accumulation, hyperphosphorylation of tau proteins, synaptic dysfunction, and inflammation of neurons. The ultimate goal of molecular biology, bioinformatics, and drug delivery systems is to provide early diagnosis and disease-modifying therapies for AD and other “normative” approaches. CircRNAs and IGF2BP3 are considered therapeutic targets for both synthetic circRNAs and antisense oligonucleotides that affect them by altering their expression or interactions with IGF2BP3 and influencing downstream effects on mRNA stability and translation. Furthermore, small molecules or gene editing technologies could be used to target IGF2BP3, thereby restoring post-transcriptional regulation and impacting multiple pathological pathways simultaneously (Li et al., 2024a). However, translating these findings to the clinical setting will be very difficult. One of the key challenges is delivering circRNA or molecules targeting IGF2BP3 via the blood-brain barrier. Various forms of advanced nanotech-based drug delivery systems, e.g., liposomes and/or exosomes, are being created for this purpose.Specificity is another issue; that is, how the intervention applies to one target, off-target effects can disrupt crucial cell functions and demand great safety testing.

Feasibility, Delivery Constraints, and Safety Considerations

While there is good reason to believe that targeting circRNAs and/or IGF2BP3 in AD may have conceptual merit, there are still many barriers that need to be overcome to bring these ideas into clinical practice. The major barrier is delivering therapeutic agents across the BBB. Systemic administration of ASOs or siRNAs has resulted in minimal penetration into the CNS. Intrathecal delivery of ASOs has been successfully demonstrated in other neurological diseases. However, gene transfer using AAVs or ligand-targeted nanoparticles may also be useful therapeutic strategies. As well, there have been investigations into using engineered extracellular vesicles as vehicles for CNS delivery. However, neither engineered extracellular vesicles nor the methods of generating them are consistent or scalable (Shirmast et al. 2024).

Off-targets represent another important flaw in targeting circRNAs therapeutically. Since circRNAs are formed from the same genomic locus as their linear host RNA transcript, there is typically a high homology of sequence; therefore, ASOs or siRNA designed to degrade circRNA may inadvertently bind to and degrade the linear mRNA that corresponds to the circRNA. Unintended inhibition of gene expression can alter normal transcriptional regulation and cellular processes, which may result in harmful functional consequences. There is also additional risk associated with CRISPR-based editing of the genome, aimed at altering circRNA formation through either altering splice sites or through altering inverted repeat sequences that allow for circularization; these alterations could alter normal splicing and/or regulatory elements that affect the transcription of the gene, resulting in a potentially unstable genome with unknown downstream molecular consequences (Yashooa et al. 2026).

Immune activation is another critical safety concern for developing RNA-based therapeutics for AD. The presence of double-stranded RNA structures in siRNAs or some ASOs can be identified by innate immune sensors and can activate pattern-recognition receptors (TLR3, TLR7, and TLR8) as well as cytosolic RNA sensors (RIG-I and MDA5), causing downstream inflammation. When these receptors are activated, they produce pro-inflammatory cytokines and type-I interferons. Other viral delivery systems, such as AAV vectors, may also cause an immune response to their use. Furthermore, repeated doses of oligonucleotide therapeutics have the potential to increase microglial activation and release of cytokines, causing increased neuroinflammation and neuronal damage in AD (Kaushal 2023; Kang et al. 2023).

Finally, the ultimate goal in evaluating therapeutic efficacy is to use reliable clinical and biomarker endpoints. Reliable clinical endpoints may include neuroimaging approaches (e.g., amyloid-β and tau PET) that allow the assessment of pathological progression and target engagement in the brain. CSF biomarkers (e.g., Aβ42, p-tau, & total tau), as well as traditional cognitive assessments, provide reliable information regarding disease progression and response to treatment in clinical trials. Long-term safety monitoring and long-term follow-up are necessary to evaluate the durability of treatment effects and overall risk-benefit profile associated with new treatments for AD (Abanto et al. 2024; Elghanam et al. 2024).

Limitations Pertinent to circRNAs and IGF2BP3 as Targets in AD

AD can be effectively managed using circRNAs and IGF2BP3, but there are numerous limitations; these limitations must be resolved if these approaches are to become viable clinical options. The limitations arise from the complex biological nature of both types of molecules, and technical restrictions on manipulating either rectifically, and thirdly, from safety/reliability issues involved with using either of them (Zhang et al. 2024).

Biological Complexity and Disease Specificity

There are thousands of different types of circRNAs, all having different roles in the brain. Yet their functions in AD pathophysiology are not fully elucidated. Also, it is important to determine whether such circRNAs are causative or merely associatedwith disease progression, as these might be redundant (Li et al. 2024a, b, c). Further, many circRNAs are pleiotropic as they may have been reported to modulate many pathways or interact with different proteins, making it impossible to predict and may influence their downstream effects upon single circRNA targeting. Similarly, IGF2BP3 functions broadly as it stabilizes a plethora of mRNAs, which are essential for regular cellular processes. Targeting IGF2BP3 without disrupting its essential actions in neurodevelopment and neuronal maintenance is challenging. IGF2BP3 over-may suppression or activation may have undesired effects, such as impairment of synaptic function or neuronal viability (Zhang et al. 2024).

Challenges in Delivery and Specificity

One of the enormous barriers is the effective delivery of circRNA or IGF2BP3targeting molecules across the BBB. The BBB restricts the entry of such agents into the CNS and requires highly cutting-edge drug delivery systems, such as viral-mediated vectors, nanoparticles, and exosomes (Bors and Erdő, 2019). While such advanced technologies are available, they do not provide an ideal solution to target particular brain areas without unwanted side effects. The specificity of circRNA-targeting therapies, including antisense oligonucleotides or small interfering RNAs, may also present problems. Most importantly, most concerns among all those pointed out are the possible off-target interaction leading to hindrances of normal gene expression (Garbo et al. 2022). CircRNAs have a great tendency towardshigh sequence homology with their linear RNA counterparts. For IGF2BP3, small molecules or any other modulator might unintentionally affect other members of the IGF2BP family, resulting in broad and potentially harmful effects.

Limited Understanding of Mechanisms

It is a matter of much research and evidence that circRNAs and IGF2BP3 are involved in AD pathology; however, the precise pathway that leads to their activity remains to be elucidated. This is detrimental to designing effective therapeutic interventions. For example, it is known that some circRNAs modulate IGF2BP3 activity, but the implication of such modulation on the neuronal resilience and progression of disease is still under exploration (Mafi et al. 2024).

Potential for Unintended Consequences

The effects of manipulating the circRNAs or IGF2BP3 of long duration remain largely unknown. As they are involved in several regulatory pathways, interventions might inadvertently disturb normal cellular homeostasis and be associated with unexpected, undesirable effects. For example, reducing IGF2BP3 activity in the phenotype will induce the reduction of Aβ production; however, this might also destabilize other important mRNAs and lead to synaptic dysfunction or neuroinflammation. Further, engineered synthetic circRNAs used as therapeutic agents may additionally perturb innate RNA regulatory networks, leading to similar imbalances in gene expression (Okholm et al. 2024).

Translational and Clinical Challenges

There are many challenges involved in translating circRNA and IGF2BP3 treatment from research labs to actual patients. Preclinical models, such as animal experiments, cannot adequately capture the full range of complexities present within the human population, especially those that create ambiguity regarding the efficacy of a treatment. In addition, it is expected that the time it takes to establish safety and regulatory pathways for new RNA-based therapies would greatly extend the time until an agent could be delivered to patients. Finally, there are significant limitations related to cost and scalability associated with producing high quality optimal scale manufacture of new delivery systems for circRNAs and/or delivery systems of IGF2BP3 targeting molecules, which could represent a significant barrier to providing an adequately priced therapy in a clinical environment (Vojgani et al. 2024).

Critical Knowledge Gaps and Future Research Directions

Emerging evidence implicates circRNAs in AD pathogenesis through regulation of Aβ, tau, and neuroinflammatory processes, yet mechanistic and translational gaps persist. CircRNA expression patterns in AD brain and biofluids are often inconsistent; for example, the direction of differential expression varies markedly between studies and brain regions, reflecting heterogeneous findings across cohorts and analytic methods (Puri et al. 2023). Some circRNAs are upregulated in AD-related brain tissue, while others are downregulated or show region-dependent expression differences. First, direct experimental validation of circRNAprotein interactions, such as with IGF2BP3 in AD models, is largely unexplored, leaving many computationally predicted networks unconfirmed. CircRNAs may play important roles in Aβ aggregation, tau hyperphosphorylation, and neuroinflammation, but their functional consequences are poorly understood (Abuduwaili et al. 2024). There has also been limited clinical validation of circRNA biomarkers in well-powered cohorts with standardized assays. The dynamics of circRNA networks over the course of disease progression are also not fully understood, limiting their utility for both biomarker discovery and therapeutic applications (Ren et al. 2022). The integration of transcriptomics, epitranscriptomics, and functional validation will be necessary to address these limitations and to define the regulatory roles that circRNAs play in AD so that they can serve as reliable diagnostic biomarkers or therapeutic targets.

Conclusion

Recent advances in CircRNA-IGF2BP3 interaction research have revealed significant complexity associated with these two molecules as it pertains to their roles in the pathophysiology of AD. Recent developments in the field have established the role of circRNAs as the mRNA sponges, protein scaffolds, and transcriptional modulators in the regulation of gene expression at post-transcriptional levels. Emerging evidence indicates that dysregulation of circRNAs is associated with neurodegenerative diseases and is influenced by family member IGF2BP3, which affects stability, localization, and translation of RNA. These interactions between circRNAs and IGF2BP3 may represent a novel pathway through which dysregulated RNA dynamics contribute to cellular dysfunction in AD. For example, while IGF2BP3 modulates the stability of certain RNA species associated with neuroinflammation, synaptic plasticity, and oxidative stress, circRNAs associated with AD may bind to and/or sequester IGF2BP3 and impair its functionality. Disruption in this regulatory interaction could exacerbate tau pathology, Aβ aggregation, and neuronal loss. Further exploration of this interaction has the potential to provide new strategies for therapeutic interventions and methods for biomarker development. Understanding the influence of circRNA-IGF2BP3 interactions on the progression of the disease will facilitate the identification of RNA-targeted therapies aimed at restoring neuronal homeostasis in AD.

CircRNAs have become interesting candidates with major diagnostic potential in the complex terrain of AD progression. Future studies with AD patients have to be more extensive if we are to progress our knowledge. These in-depth studies should try to determine the exact phases of ADand pinpoint particular brain areas and cell types that are altered in the context of AD in a particular manner. Employing a thorough approach, researchers will be able to investigate the complex interaction between circRNA changes and the physiological and pathological development of AD. This comprehensive review may explore the traditional, undiscovered aspects of AD pathogenesis in both preclinical and clinical practice, and it may even lead to the discovery of novel biomarkers.

Abbreviations

AAV

Adeno Associated Virus

AD

Alzheimer’s disease

APP

Amyloid Precursor Protein

ASO

Anti-sense oligonucleotide

ATG4-B

Autophagy-related 4B cysteine peptidase

AUC

Area Under the Curve

Aβ

Amyloid beta

BACE1

Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1

BACE1

β-secretase 1

BBB

Blood-Brain Barrier

BDNF

Brain-derivedneurotrophic factor

BSJ

Back Splice Junction

CircRNA

Circular RNA

CNS

Central Nervous System

CRISPR

Clustered regularly interspaced short palindromic repeats

CSF

Cerebrospinal Fluid

DNM1

Dynamin-1

ER

Endoplasmic reticulum

EVs

Extracellular vesicles

FoxO3

Forkhead box O3

GSK-3β

Glycogen synthase kinase-3

IGF2BP3

Insulin-like Growth Factor 2 mRNA-Binding Protein 3

lncRNA

Long non-coding RNA

MAPT

Microtubule-associated protein tau

miRNA

MicroRNA

mRNA

Messenger RNA

ncRNA

Non-coding RNA

NFTs

Neurofibrillary tangles

NF-κB

nuclear factor-kappa beta

NPV

Negative Predictive Value

NTRK2

Neurotrophic receptor tyrosine kinase 2

PPV

Positive Predictive Value

RBP

RNA-Binding protein

RNA

Ribonucleic acid

ROC

Receiver operating characteristic

ROS

Reactive oxygen species

RTN4

Reticulon 4

siRNAs

Small-interfering RNAs

Sirt1

Sirtuin 1

sncRNA

Small non-coding RNA

Sry

Sex-determining region Y

Tau

Tau protein

Author Contributions

S.M.F.: Conceptualisation, literature search, data extraction, drafting of manuscript, reviewed draft manuscript, and certified final manuscript; S.N.S.J.: Conceptualisation, literature search, data extraction, and drafting of manuscript; S.M. and P.P.: Literature search, drafting of manuscript, and preparation of figures.

Funding

Not applicable as it is a literature review.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors declare no competing interests.

Ethical Approval

Not applicable.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.