AD is the most common neurodegenerative disorder worldwide and is responsible for 60–70 % of dementia cases (DeTure and Dickson, 2019). Over 55 million individuals worldwide are estimated to have dementia in 2023, and as the world's population ages, that figure by 2050 is expected to increase to 139 million (Nichols et al., 2022). Progressive cognitive decline, memory impairment, and behavioural disturbances leading to complete loss of independence and death define AD (Tarawneh and Holtzman, 2012). Dementia is a heavy burden upon society and the economy, with an annual global burden of dementia care of over one trillion dollars (Wimo et al., 2023). However, despite intensive research, effective disease-modifying treatments have eluded developers, where current therapies are generally aimed at symptom management rather than halting or reversing disease progression (Yiannopoulou and Papageorgiou, 2020). AD pathologically is characterized by two hallmarks: intracellular NFTs and extracellular Aβ plaques (Murphy and LeVine 3rd, 2010). Tau, a microtubule-associated protein (MAP), is abnormally hyperphosphorylated and makes up the bulk of NFTs that stabilize the neuronal cytoskeleton (Iqbal et al., 2010). Normally, Tau binds and supports the microtubule's intracellular transport and maintains axonal integrity (Kadavath et al., 2015). In contrast, Tau undergoes large-scale phosphorylation in AD and is disengaged from microtubules, forming insoluble tangles that subsequently cause neuronal dysfunction (Mietelska-Porowska et al., 2014). By pathological transformation of Tau, this intracellular transport is disrupted, and synaptic function is compromised, resulting in neuronal death (Hoover et al., 2010). Tau pathology correlates strongly with the severity of cognitive decline and is thus a critical therapeutic target in AD (Schöll et al., 2019).

Tau hyperphosphorylation in AD is an intricate and multifaceted process with the molecular mechanism of which is unclear, but recently, a central player in that process has been GSK-3β (Llorens-Martín et al., 2014; Bhat et al., 2024a). One of the primary groups of enzymes responsible for phosphorylating Tau at multiple epitopes associated with the formation of NFTs is GSK-3β, a serine/threonine kinase (Amaral et al., 2021b). The secretion of this enzyme is abundant in the brain, and it is of great importance for multiple physiological functions, including energy metabolism, synaptic plasticity, and neuronal development (Falkowska et al., 2015). It, however, has profound pathological consequences when its dysregulation occurs during aging and AD progression (Xia et al., 2018). In conditions of the aging brain, GSK-3β normally becomes aberrantly activated due in part to impairments in regulating the negative Ser9 site of GSK-3β by both reduced phosphorylation and the positive side of GSK-3β phosphorylation at Tyr216 (Sayas and Ávila, 2021b). Tau hyperphosphorylation induced by chronic GSK-3β activation promotes the aggregation of Tau into NFTs and the destabilization of microtubules (Toral-Rios et al., 2020). It further was found that GSK-3β is critical for Aβ pathology by modulating the APP processing (Reddy, 2013). Alongside being activated by Aβ itself, it is also a potent activator and enhances the production of Aβ peptides, leading to a toxic, positive feedback loop that accelerates disease progression (Mohamed Asik et al., 2021). This discovery demonstrates GSK-3β as a molecular bridge connecting the Tau and Aβ pathology (Sayas and Ávila, 2021a).

Given that GSK-3β dysregulation both directly and in concert with Aβ and Tau pathologies implicates GSK-3β beyond its role in Aβ and Tau pathologies, it is important for neuronal health (Reddy, 2013). In addition to interfering with PI3K/Akt and Wnt pathways, both vital to neuronal survival, synaptic integrity, and neuroprotection, it inhibits protein kinase D (Marchetti, 2018). Aberrant activation of these pathways results in unopposed oxidative stress, neuroinflammation, and mitochondrial dysfunction, which accelerate neuronal damage and cognitive decline (Jurcău et al., 2022; Bhat et al., 2024c). However, as a major contributing factor, aging amplifies these effects by impairing neurotrophic signaling, increasing oxidative stress, and promoting chronic inflammation, which induces GSK-3β activation (Bhat et al., 2024b; Zhao et al., 2024). As both therapeutic and toxic activators of GSK-3β, recent research has studied small molecule inhibitors like lithium and tideglusib, natural compounds such as curcumin and geniposide, and new ways of miRNA modulation and immune regulation (Bhat et al., 2023b; Kühl et al., 2024). Preclinical models have demonstrated the promise of these interventions in reducing GSK3β activity, alleviating Tau pathology, and attenuating Aβ toxicity (Jitendra Joshi and Raja Sekhar Reddy, 2024). But much remains to be achieved before realistic clinical translation, like achieving isoform-specific inhibition, preserving the physiological function of GSK 3 β, and optimizing drug delivery to the brain (Wang et al., 2022).

This review will summarize the role of GSK-3β in AD, from its participation in Tau pathology, Aβ toxicity, and neurodegeneration. We seek to elucidate the mechanistic underpinnings of the dysregulation of GSK-3β during aging and its relationship with AD pathology to highlight the therapeutic potential of targeting GSK-3β.