Neurodegenerative diseases (NDDs) are characterized by the progressive loss of neurons in the nervous system. These diseases typically cause damage to the brain and spinal cord, which in turn affects various physiological functions such as cognition, movement, perception, the autonomic nervous system, and even breathing and circulation (Dugger and Dickson, 2017). NDDs include Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Amyotrophic lateral sclerosis (ALS), among others (Boland et al., 2018). Symptoms of these conditions worsen over time. Treatment focuses on improving patients’ quality of life by alleviating symptoms, but there is currently no effective cure. Increasing evidence suggests that changes occur in the activity and levels of GSK-3β in NDDs, and the GSK-3β signaling pathway is now recognized as a key signaling pathway promoting neurodegeneration. Inhibition of GSK-3β has emerged as a promising therapeutic approach for NDDs (Rippin and Eldar-Finkelman, 2021).

Glycogen synthase kinase-3 (GSK-3) was initially discovered for its ability to phosphorylate glycogen synthase and regulate glucose metabolism in response to insulin. Subsequent studies have shown that it is a widely expressed serine/threonine kinase that can phosphorylate over 100 protein substrates and is located at the intersection of many signaling pathways (Beurel et al., 2015). Encoded by two different genes located on chromosomes 19 and 3, GSK-3 has two unique isoforms: GSK-3α (51 kDa) and GSK-3β (47 kDa). These isoforms share a striking 97% amino acid sequence identity within the catalytic domain and 84% overall amino acid sequence similarity, suggesting potential common biological functions. For example, they regulate cell signaling, participate in biological metabolism, cell growth, proliferation, and differentiation, and are critical regulatory factors in many neurodevelopmental processes (Marosi et al., 2022). GSK-3β exhibits high levels of expression in the central nervous system (CNS; Yao et al., 2002). The kinase activity of GSK-3β is regulated by phosphorylation. Within the cell, serine kinases such as protein kinase B (PKB/AKT) and AMP-activated protein kinase (AMPK) target the 9th serine residue (Ser9) of GSK3β, resulting in its phosphorylation (pGSK-3β-Ser9) and subsequent inactivation. In contrast, tyrosine kinases can phosphorylate the 216th tyrosine residue (Tyr216) of GSK-3β (resulting in pGSK-3β-Tyr216), leading to a fivefold increase in its enzymatic activity. GSK-3β interacts with numerous molecules intricately associated with NDDs, including hippocampal cell proliferation, neuronal development and regeneration, cell cycle regulation, and neuronal polarization (Pardo et al., 2016; Demuro et al., 2021; see Figure 1).

AD is the most common neurodegenerative disease, encompassing 60–80% of global dementia cases (Gauthier et al., 2022). Cognitive and non-cognitive symptoms are prominent clinical features. Early stages manifest with challenges in recalling recent discussions, names, events, emotional responses, or even depressive symptoms, which evolved into communication impairments, confusion, compromised decision-making, and behavioral alterations. As the disease advances, walking difficulties, speech impairments, and swallowing problems become prevalent (Breijyeh and Karaman, 2020). Regarding genetic characteristics, Alzheimer’s disease (AD) can be categorized into familial and sporadic forms. Familial AD is associated with mutations in three genes: APP, PSEN1, and PSEN2. Sporadic AD is the most prevalent form (Uddin et al., 2021). It has prompted various hypotheses elucidating its onset, encompassing the cholinergic, amyloid, Tau protein proliferation, mitochondrial cascade, inflammation, and neurovascular hypotheses. The pathological features include the formation of senile plaques composed of amyloid-β (Aβ) and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated Tau (Penke et al., 2019; Kent et al., 2020). This aggregation of Aβ and Tau detrimentally affects synaptic plasticity and triggers neuronal cell demise (Scheltens et al., 2021). Elevated GSK-3β activity has been observed in the brains of AD patients and various AD mouse models. Upregulation of GSK-3β has been shown to instigate AD pathology, cognitive decline, and glial cell proliferation (Albeely et al., 2022; Chauhan et al., 2022).

Parkinson’s disease is a progressive neurodegenerative disorder with significant morbidity and mortality (Halli-Tierney et al., 2020). The pathological hallmark of PD is the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the accumulation of misfolded α-synuclein (Armstrong and Okun, 2020). Cardinal motor symptoms such as tremors, rigidity, bradykinesia, and postural instability are typically observed. PD can also present with non-motor symptoms (NMSs), including sleep disorders, constipation, urinary dysfunction, orthostatic hypotension, cognitive decline, depression, and anxiety (Schapira et al., 2017). Multiple pathways and mechanisms are involved in the molecular pathogenesis of PD, including α-synuclein deposition, oxidative stress, mitochondrial function, calcium homeostasis, axonal transport, and neuroinflammation (Balestrino and Schapira, 2020). Both environmental and genetic factors have been found to contribute to the development of PD (Yuan et al., 2022). Notably, the activity of GSK-3β is elevated in the striatum of PD patients compared to controls, indicating the involvement of GSK-3β in the pathogenesis of PD.

HD is a rare autosomal dominant genetic disorder resulting from the abnormal expansion of CAG trinucleotide repeats in the Huntingtin gene on the chromosome (Tabrizi et al., 2020). This expansion triggers the toxic form of the Huntingtin protein, leading to synaptic impairment, mitochondrial dysfunction, and disrupted axonal transport, ultimately contributing to motor, cognitive, and psychiatric impairments (Baake et al., 2017; Ghosh and Tabrizi, 2018). Emerging research also suggests that HD may be classified as a secondary tauopathy, with tau insoluble aggregates observed in late-stage HD (Salem and Cicchetti, 2023). Furthermore, there is increased activity of pGSK-3β-Tyr216 in the hippocampus of HD patients and mice, underscoring the potential significance of abnormal GSK-3β signaling in HD progression (L'Episcopo et al., 2016).

ALS, also known as Lou Gehrig’s disease, is a neurodegenerative disorder that primarily affects motor neurons in the spinal cord, brainstem, and motor cortex, resulting in the gradual weakening of the muscles and eventually respiratory failure. The cause of ALS is unknown, with suggested involvement of signaling pathway alterations and factors such as protein misfolding and misassembly, mitochondrial dysfunction, oxidative stress, and neuroinflammation (Sever et al., 2022). ALS is divided into two types, with approximately 90–95% being sporadic cases (sALS) and the remaining 5–10% being familial cases (fALS) (Prasad et al., 2019). Research has found an increase in the levels of GSK-3β and phosphorylated GSK-3β at Tyr216 in the frontal cortex and hippocampus of ALS patients (Yang et al., 2008). GSK-3β is believed to affect the superoxide dismutase SOD1 gene and TAR DNA binding protein 43 (TDP-43), thus promoting the progression of ALS.

Neuroinflammation is considered a contributing factor in NDDs (Gianferrara et al., 2022; Samim Khan et al., 2023). GSK-3β is a nexus for various signaling pathways, recognized as a pivotal inflammation regulator. Microglia activation and heightened proinflammatory cytokines define brain inflammation. Activated microglia release proinflammatory and neurotoxic agents, intensifying neuron harm through oxidative stress and cytokine toxicity (Kwon and Koh, 2020; Bennett and Sloan, 2021). GSK-3β activation stimulates microglia, amplifying inflammatory cytokine production, culminating in neuronal demise (Beurel, 2011; Cao et al., 2017). This perpetuates an ongoing inflammatory response, indicating GSK-3β’s vital role in the harmful feedback loop with microglia and impaired neurons. Inhibiting GSK-3β enhances tolerance to inflammation, curbing repeated cytokine release, and ameliorating symptoms in inflammatory conditions (Wang et al., 2013; Beurel et al., 2015). These findings underscore GSK-3β’s involvement in microglia-mediated neuroinflammation and neuronal death.

Mitochondria play a crucial role in the development and progression of NDD (Johnson et al., 2021). Mitochondria can synthesize ATP and regulate cellular apoptosis, ferroptosis, and inflammasome activation. Deficits in mitochondrial biogenesis may contribute to dysfunction in various neurodegenerative conditions. Drp1 is key in maintaining healthy mitochondrial dynamics by inducing fission through contraction and GTPase activity (Kleele et al., 2021). GSK-3β triggers GTPase activity by phosphorylating Drp1 at Ser40 and Ser44, resulting in fragmented mitochondria (Yan et al., 2015). Furthermore, mitochondrial dysfunction-induced hydrogen peroxide further activates GSK3β, exacerbating disease progression. Inhibition of GSK3β-induced phosphorylation can protect mitochondria, maintain energy metabolism, and rescue memory impairment in transgenic mice (Baek et al., 2017). In summary, overactive GSK-3β disrupts mitochondrial function and energy production, leading to neurodegeneration.

Recent studies have also suggested potential links between GSK-3β dysregulation and other neuropsychiatric disorders, such as schizophrenia, depression, and anxiety (Cole, 2013; Tamura et al., 2016). Disrupted-in-schizophrenia 1 (DISC1) is associated with schizophrenia, and its deficiency causes behavioral abnormalities in mice (Johnstone et al., 2011). DISC1 also interacts with Translin-associated protein X (TRAXd), and GSK-3β regulates the function of DISC1/TRAXd (Weng et al., 2018). Inhibiting GSK-3β can protect DNA and restore neuronal function, thereby preserving neuron (Chien et al., 2018). Dysregulation of brain serotonin (5-HT) function is one of the pathogenic mechanisms of depression and anxiety (Carhart-Harris and Nutt, 2017). Increasing evidence has shown that GSK-3β acts as a modulator in the serotonin neurotransmission system, including direct interaction with serotonin 1B (5-HT1B) receptors in a highly selective manner and a prominent modulating effect on 5-HT1B receptor activity. Inactivation of GSK-3β in the brain by either pharmacological or genetic methods leads to amelioration of the abnormal behavior resulting from 5-HT deficiency (Beaulieu et al., 2008; Zhou et al., 2012). Therefore, targeting GSK-3β and related signaling pathways may provide therapeutic advantages for treating certain DISC1- and 5-HT-related neuropsychiatric disorders.

GSK-3β plays a crucial role in many neurological disorders. GSK-3β may serve as a promising therapeutic target for treating diseases, promoting recovery, and maintaining organism stability (Rippin and Eldar-Finkelman, 2021). Several categories of GSK-3β inhibitors have been developed (Wadhwa et al., 2020), including (1) magnesium-competitive inhibitors; (2) ATP-competitive inhibitors; (3) substrate-competitive inhibitors; and (4) regulators of GSK-3β Ser9 phosphorylation.

The currently used drugs for AD, including cholinesterase inhibitors and NMDA receptor antagonists, only mildly alleviate the symptoms but do not halt or delay the progression of the disease (Birks and Harvey, 2018; McShane et al., 2019). Lithium salts are one of the earliest drugs used for AD treatment and can inhibit GSK-3β and reduce Tau phosphorylation and amyloid production but they have poor efficacy for mild AD patient (Hampel et al., 2009). The selective inhibitors SB216763 and FLZs can reduce Tau phosphorylation and protect neurons from the toxicity of Aβ oligomers, improving spatial memory (Bao et al., 2013; Deng et al., 2014). Noncompetitive irreversible Adenosine Triphosphate (ATP) inhibitor derivatives of 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD), such as Tideglusib and TDZD-8, can stimulate GSK-3β Ser9 phosphorylation, thereby reducing Tau and amyloid deposition (Domínguez et al., 2012). Although there are many potential inhibitors available for AD treatment, few have succeeded in clinical trials (Chauhan et al., 2022).

GSK-3β inhibitors, including SB216763, lithium chloride, and TDZD-8, have demonstrated significant effects in the treatment of PD. These inhibitors efficiently inhibit the generation of proinflammatory cytokines such as TNF-α and IL-12 while promoting the production of anti-inflammatory cytokines such as IL-10 (Coant et al., 2011), which helps protect dopaminergic neurons from neurotoxicity, preserve mitochondrial function, and eliminate oxidative damage in PD model (Chiu et al., 2014). Additionally, GSK-3β inhibitors can promote the proliferation of neural progenitor cells and stimulate neurogenesis, playing a role in neural regeneration and repair (Eom and Jope, 2009). Therefore, GSK-3β inhibitors have broad application prospects in the treatment of PD.

GSK-3β inhibition has emerged as a potential therapeutic approach for HD (D'Mello, 2021). Studies have revealed GSK-3β’s association with mHtt aggregation in HD mice and neurons (Valencia et al., 2010). Elevated GSK-3β expression and activity in the hippocampus of HD patients and mouse models correlate with increased tau phosphorylation (L'Episcopo et al., 2016). In cellular and mouse HD models, GSK-3β silencing and inhibition reduce mutant huntingtin aggregates and neuronal death, while selective GSK-3 inhibition improves motor function and neuroprotection (Rippin et al., 2021). Lithium, a GSK-3β inhibitor, exhibits beneficial effects in preclinical HD models, enhancing motor function and mitigating striatal deficits (Snitow et al., 2021). Co-treatment with lithium and valproate further alleviates HD-associated deficits (Chiu et al., 2011). These findings underscore GSK-3β’s relevance in HD pathogenesis, driving ongoing exploration of its therapeutic potential.

GSK-3β inhibitors have been studied as potential therapies for ALS in vivo. It has been shown that lithium treatment can prevent apoptosis, alleviate motor function defects, and slow disease progression in SOD1-G93A mice (Shin et al., 2007). Another potential therapeutic option for ALS is valproic acid (VPA), which has been shown to slow disease progression and increase lifespan in SOD1-G93A mice (Sugai et al., 2004). Combined therapy with lithium and VPA shows greater rescue effects on motor dysfunction and disease progression in the SOD1-G93A mouse model (Jiang et al., 2016). These findings indicate that GSK-3β holds great potential as a therapeutic target for ALS.

NDDs such as AD, HD, PD, and ALS are increasingly recognized as major contributors to death and disability worldwide (Carroll, 2019). Although these four common NDDs exhibit different clinical profiles, they share common molecular pathogenic mechanisms. These mechanisms encompass proteostasis, cellular signaling pathways, neuroinflammation, and mitochondrial deficits, suggesting converging pathways of neurodegeneration (Durrenberger et al., 2015; Noori et al., 2021). GSK-3β plays a pivotal role in multiple NDDs. In AD, GSK-3β influences the processing of APP and hyperphosphorylation of Tau protein, contributing to Aβ plaque formation and neurofibrillary tangle development. In PD, GSK-3β affects α-synuclein aggregation and dopamine receptor signaling. In HD, GSK-3β contributes to Tau pathology and GABAergic dysfunction. In ALS, GSK-3β impacts TDP-43 pathology and the Wnt signaling pathway. The intricate involvement of GSK-3β in the pathogenesis of various NDDs underscores its significance as a potential therapeutic target. GSK-3β inhibitors have the potential to protect neurons in various disease models. In conclusion, by unraveling its diverse functions and their interactions, we can advance our understanding of disease mechanisms and design targeted strategies to counteract neurodegeneration.

The diverse functions of GSK-3β in controlling protein aggregation, mitochondrial dysfunction, neuroinflammation, and cellular signaling contribute to a comprehensive understanding of disease mechanisms. Although GSK-3β’s involvements in AD, PD, HD, and ALS are established, its potential impact on other neurodegenerative and neuropsychiatric disorders presents an intriguing field for further investigation (Lin et al., 2020).

The interactions of GSK-3β with the Wnt pathway, dopamine receptor signaling, and various kinases are intricately complex. Delving into these interactions deepens our understanding of potential molecular mechanisms and may unveil novel treatment strategies. Selectively modulating the activity of specific cellular pools of GSK-3β or its specific downstream or upstream partners may offer effective approaches for combating neurodegenerative diseases. Thus, GSK3β and its signaling pathway partners hold great promise as therapeutic targets for a multitude of neurological disorders.

A global endeavor is currently in progress to discover more effective methods for clinically managing NDDs, aiming to delay their onset and hinder their progression. Inhibition of GSK-3β was considered a promising therapeutic approach. However, most GSK-3β inhibitors that were developed function as ATP competitive inhibitors, with typical limitations in specificity, safety, and drug-induced resistance. Clinical and preclinical trials with GSK-3β inhibitors have shown limited effectiveness (Llorens-Martín et al., 2014; Xia et al., 2021). Thus, more selective and potent GSK-3β inhibitors should be developed, which can effectively target pathological processes and spare essential physiological functions. Additionally, considering the complex nature of NDDs, it appears that single-target drugs might fall short of achieving satisfactory therapeutic outcomes. Multi-target design strategy may potentially enhance both therapeutic safety and efficacy (Zhang et al., 2019; Gontijo et al., 2020).

HY wrote the draft. MX revised the manuscript. ZZ conceived the manuscript and made revisions. All authors contributed to the article and approved the submission.

This work was supported by grants from the Innovative Research Groups of Hubei Province (2022CFA026) and the National Natural Science Foundation of China (Nos. 82271447 and 81901090).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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