Abstract
Zinc is an essential trace element that plays a critical role in synaptic transmission, neuronal survival, gene regulation, and antioxidant defence in the brain. Hence, one of the central contributors to Alzheimer’s disease (AD) pathology is the disruption of zinc homeostasis. Recent studies suggest that an interconnected regulatory network maintains neuronal stability, comprising zinc-binding proteins, such as metallothioneins, zinc-dependent enzymes, zinc finger transcription factors, and zinc transporters. The accumulation of amyloid-β, Tau hyperphosphorylation, mitochondrial dysfunction, oxidative stress, and chronic neuroinflammation are the underlying causes of the mislocalization of zinc in AD. Also, the involvement of zinc-associated enzymes influences the amyloid clearance, as well as transcriptional regulation, which disrupts neuronal proteostasis. Hence, the therapeutic strategies usually aim at restoring the zinc balance, which involves the small-molecule metal modulators, natural phytochemicals with zinc-interacting properties and gene-based approaches. Hence, understanding zinc-binding protein networks provides a system-level framework for developing multi-target therapeutic interventions that could slow rapid progression, as well as might increase neuronal resilience in AD.
1 Introduction
The essential trace elements, like zinc, play a fundamental role in synaptic transmission, brain development, and neuronal survival (Li et al., 2022; Chamakioti et al., 2024). The human brain has been found to contain the highest zinc concentration in the body, particularly in the cerebral cortex and hippocampus regions, which are associated with memory and cognition (Choi B. Y. et al., 2020). Quantitatively, zinc is one of the most abundant trace metals in the brain, with total concentrations estimated to range between ∼150 and 200 μM, particularly enriched in the hippocampus and cerebral cortex (Piechal et al., 2016). Importantly, zinc exists in distinct pools, including tightly protein-bound zinc and a labile, synaptic vesicular pool that can reach transient concentrations of up to ∼1 mM during neuronal activity (Li et al., 2017). Krall et al. (2021) in their study suggested that zinc is found in both protein-bound and labile synaptic pools, which allows zinc to serve as a neuromodulator, and the biochemical characteristics of zinc allow it to stabilise protein structure that helps to control the activity of enzymes and expression of genes. Therefore, the zinc-binding protein plays an interconnection to maintain neuronal homeostasis and protects against cellular stress (Chen et al., 2024; Cai C. et al., 2025). Kluska et al. (2018) suggested that zinc-binding proteins are structurally heterogeneous macromolecules, which bind zinc ions using cysteine, histidine or aspartate residues and form stable metal-protein complexes. Zinc also plays a structural role in stabilising transcription factors and signalling proteins, which supports proper folding and maintains functional integrity (Chen et al., 2024; Pavić Vulinović et al., 2026). In addition to its structural roles, zinc acts as an essential catalytic element for numerous enzymes, which are involved in metabolic regulation, antioxidant defence and synaptic remodelling (Wang et al., 2023). Along with Zinc binding domains, which also control transcriptional processes that are crucial for neuronal differentiation, plasticity and repair. Therefore, maintaining the balance between zinc-binding proteins and zinc availability activity is also crucial for preventing synaptic function and neurodegenerative diseases (Li X. et al., 2025). Abnormal zinc buildup has been seen in amyloid plaques, where zinc ions directly bind to amyloid β (Aβ) peptides, promoting aggregation and plaque stability (Yoo et al., 2025). As a result, disrupting zinc homeostasis has become a notable aspect of AD. Chang et al. (2018) suggested that zinc-induced conformational changes accelerate Aβ oligomerisation, which in turn leads to enhanced neurotoxicity and impaired synaptic communication; also, the Tau hyperphosphorylation and neurofibrillary tangle formation may also be caused by zinc dysregulation (Nguyen et al., 2022). Hence, the zinc influences the kinase and phosphatase activity, indirectly modulating Tau phosphorylation and leading to cytoskeletal destabilisation (Zhang et al., 2022). The mechanism of oxidative stress also represents another major axis through which zinc imbalance exacerbates AD progression. Zinc-dependent enzymes are also essential components of antioxidant defence systems, including superoxide dismutases and metallothioneins (Briassoulis et al., 2023). When this zinc-binding capacity is compromised, it leads to mitochondrial dysfunction and inflammatory cascades (Liu et al., 2021). Hein et al. (2025) and Chen et al. (2025) suggested that synaptic loss and neuronal death, hallmarks of cognitive decline in AD, may be due to zinc dysregulation, which appears to play an active role in early disease stages. In experimental models, the use of metal chelators and ionophores that modulate zinc levels might reduce the amyloid load and restore synaptic function (Yoo et al., 2025; Vilella et al., 2020). Reducing zinc is needed, but complete depletion can be harmful; so, selective targeting of zinc-binding proteins and transporters is key to pathological signalling (Hunsaker and Franz, 2019; Dharmasivam and Kaya, 2025). Zinc-binding proteins play a key role in structural stability, transcriptional control and enzymatic regulation in neurons (Consales et al., 2024; ), and their dysfunction in AD contributes to Tau pathology, amyloid aggregation and oxidative damage (Gulisano et al., 2018; Ma et al., 2022). Yang, (2025) reported that in AD, the zinc accumulation is not merely a passive consequence but arises from dysregulation of zinc transporters, especially by reduction of ZnT3, leading to impaired vesicular sequestration and excessive synaptic zinc release. The extracellular zinc readily binds to amyloid-β via histidine residues, promoting aggregation and plaque stabilisation (). Additionally, the synaptic zinc contributes to excitotoxicity by modulating glutamatergic neurotransmission through the co-release of glutamate (Granzotto et al., 2020). Moreover, under pathological conditions, they can enter the postsynaptic neurons through calcium-permeable channels, which disrupts the NMDA and AMPA receptor functions (Krall et al., 2020).
2 Zinc-binding proteins and Alzheimer’s disease
In AD, multiple zinc-dependent protein families contribute to disease progression due to their influence on amyloid metabolism, synaptic plasticity and neuronal survival pathways. Hence, the dysregulation of zinc-dependent proteins reflects disease-specific molecular adaptations as well as altered zinc homeostasis (Padjasek et al., 2020; Wang et al., 2020) as shown in Table 1.
TABLE 1
| Protein class | Key members | Brain localisation | Mechanism in AD | Functional impact | Therapeutic relevance |
|---|---|---|---|---|---|
| Metallothioneins | MT-1, MT-2, MT-3 | Neurons, astrocytes | Reduced MT-3 → impaired zinc buffering → increased free Zn2+ | Promotes Aβ aggregation, oxidative stress | Target for antioxidant + gene therapy |
| Zinc-dependent enzymes | Neprilysin, IDE, MMPs | Extracellular, synaptic | Zn dysregulation → reduced enzymatic activity | ↓ Aβ clearance, ↑ plaque accumulation | Enzyme activation strategies |
| Zinc finger proteins | ZNF family | Nucleus | Zn imbalance → transcriptional dysregulation | Impaired neuronal survival pathways | Epigenetic modulation |
| Zinc transporters | ZnT3, ZIPs | Synaptic vesicles, membranes | ZnT3 ↓ → altered vesicular Zn release | Synaptic dysfunction, Tau kinase activation | Transporter-targeted therapy |
Major zinc-binding protein classes implicated in Alzheimer’s disease.
2.1 Metallothioneins
The primary regulator of intracellular metal homeostasis is the metallothioneins, which are small, cysteine-rich zinc-binding proteins; their high thiol content enables them to bind zinc with exceptional affinity, which functions as a dynamic metal reservoirs that buffer fluctuations in cytosolic zinc levels (Rodríguez-Menéndez et al., 2018; Rodríguez-Menéndez et al., 2018). Moreover, in glial cells and neurons, metallothioneins (MTs) are a family of low-molecular-weight, cysteine-rich proteins (MT-1, MT-2, MT-3, and MT-4) that regulate intracellular metal homeostasis through high-affinity zinc binding. Among these, MT-3 is a neuron-specific isoform predominantly expressed in the central nervous system and plays a critical role in synaptic plasticity and neuronal survival (Vašák and Meloni, 2017; Miyazaki and Asanuma, 2023). In AD, the brain regions get affected due to altered metallothionein expression; these proteins usually detain the excess zinc released during the synaptic dysfunction, which inhibits the zinc-induced excitotoxicity and aggregation of amyloid peptides (Juárez-Rebollar et al., 2017; Xu et al., 2019). Moreover, the metallothioneins reduce the oxidative damage as they may scavenge reactive oxygen species and mitigate lipid peroxidation (Rios et al., 2018; Yang et al., 2024). Fasae et al. (2021) suggested that the metallothioneins are protective; their dysregulation can impair their buffering function, which contributes to prolonging the oxidative injury and inflammatory signalling. Moreover, the apoptosis and immune response pathway expression is influenced by metallothioneins, interconnecting the metal homeostasis to broader neurodegenerative mechanisms (Krezel and Maret, 2021; Schulz and Rink, 2025). Mocchegiani et al. (2002) reported that impaired zinc deficiency disrupts caspase inhibition and NF-κB- mediated immune response, which in turn promotes neuronal apoptosis and chronic neuroinflammation. Additionally, in a study by Cai et al. (2023), the metal mixtures demonstrated that combined exposure to metals such as Mn, Pb and As induces synergistic neurotoxicity, partly by disrupting zinc homeostasis in C.elegans. Furthermore, MT-3 levels are significantly reduced in the AD brain, particularly in regions associated with amyloid plaque deposition (Vašák and Meloni, 2017). The neuronal capacity to buffer excess zinc is compromised due to the reduction, which leads to an increase in the availability of free zinc ions that promote amyloid-β aggregation and oxidative stress (Boopathi et al., 2020). Additionally, under oxidative stress, metallothioneins can release bound zinc that amplifies intracellular zinc toxicity, which exacerbates neuronal injury (Tran and Lee, 2025).
2.2 Zinc-dependent enzymes
The enzymes rely on zinc as a catalytic cofactor, which in turn stabilises transition states, and among these, the matrix metalloproteinases (MMPs) and other zinc proteases play a vital role, as it remodels extracellular matrix and amyloid metabolism (Cabral-Pacheco et al., 2020; Ruz et al., 2023). One of the potential protective functions of the MMPs is to degrade amyloid-β peptides; along with that, they also contribute to synaptic plasticity by regulating the pericellular proteolysis, which leads to dysregulation of MMP activity, causing disruption of BBB integrity and promoting neuroinflammation (de Almeida et al., 2022; Hu et al., 2025). Mukherjee and Das (2024) suggested that elevated expression of MMP in AD is associated with the chronic inflammatory responses, which indicates that balanced enzymatic activity is essential for maintaining neural tissue homeostasis. The enzymes involved in Aβ clearance, such as neprilysin and insulin-degrading enzymes (IDE), reduce the zinc-dependent protease activity, which correlates with increased amyloid accumulation in ageing and AD (Gerber et al., 2017; Saxena et al., 2024). Mechanistically, both neprilysin and insulin-degrading enzyme are zinc-dependent metalloproteases that require optimal zinc coordination for catalytic activity (Qu et al., 2026). Dysregulation of zinc homeostasis, either through deficiency or mislocalisation, impairs their enzymatic function, leading to reduced amyloid-β degradation and subsequent accumulation (Shippy et al., 2024). This establishes a direct functional link between zinc imbalance and defective proteolytic clearance pathways in AD, highlighting that zinc dysregulation contributes not only to amyloid formation but also to impaired amyloid removal (Yadav et al., 2026). Also, the activity linked to the metal homeostasis is associated with amyloid degradation, amyloid metabolism and hence the availability of zinc and its enzymes regulates the antioxidant systems, mitochondrial respiration and signal transduction (Kim and Lee, 2021; Xu et al., 2025).
2.3 Zinc finger proteins
The largest families of transcriptional regulators in the human genome are the zinc finger proteins, and these proteins contain zinc-coordinating motifs that stabilise DNA and RNA-binding domains, enabling precise control of gene expression (Rakhra and Rakhra, 2021). The processes in neurons, such as differentiation, synaptic plasticity and stress responses, are regulated via zinc finger transcriptional factors, and the alteration in zinc finger protein activity leads to transcriptional dysregulation in AD (Bu et al., 2021; Wang et al., 2025). Hence, the epigenetic modifications and oxidative stress can impair zinc finger stability, which disrupts the gene and may modulate the pathways associated with inflammation, apoptosis and amyloid processing (Su et al., 2022). Additionally, the zinc finger RNA-binding proteins influence mRNA stability and translation, which in turn have become one of the major hallmarks of neurodegenerative disorder suggessting the zinc-dependent transcription as a vital role in maintaining the neuronal proteostasis (Kamaliyan and Clarke, 2024; Rummens and Da Cruz, 2025).
2.4 Zinc transporters
The transporters from SLC30 and SLC39 families regulate the cellular zinc distribution by controlling the influx, efflux and compartmentalisation; these transporters also maintain synaptic zinc gradients, which are essential for neurotransmission and plasticity (; Barman et al., 2026). Also, in the hippocampal neurons, the vesicular zinc that is released during the synaptic activity modulates the receptor function and intracellular signalling cascades, and the restoration of zinc homeostasis has been shown to enhance synaptic signalling pathways such as BDNF-TrkB and improve neruonal functions (Rychlik and Mlyniec, 2020; Yue et al., 2020), along with the reduced ZnT3 levels, which influence the alteration in synaptic zinc storage and lead to impaired cognitive function. ZnT3 plays a pivotal role in loading zinc into synaptic vesicles, and its downregulation in AD disrupts synaptic zinc signalling and long-term potentiation (McAllister and Dyck, 2017). Experimental evidence suggests that loss of ZnT3 alters synaptic plasticity and accelerates cognitive decline, while dysregulated zinc release enhances amyloid aggregation and neurotoxicity (). Furthermore, altered ZnT3-mediated zinc signalling has been linked to downstream activation of Tau-related kinases, including GSK-3β, thereby integrating synaptic zinc imbalance with both amyloid and Tau pathologies (Chacon et al., 2019). Even the extracellular zinc can accelerate amyloid aggregation, whereas intracellular zinc deficiency compromises enzymatic and transcriptional processes (Lei et al., 2021). The neuroinflammatory diseases are influenced by imbalanced zinc transporters, which highlights the need for balanced zinc levels required for neuronal health (Li et al., 2026). Therefore, Miao et al. (2023) and Chao et al. (2025) suggested that therapeutic strategies targeted at restoring transporter expression and function may provide multifaceted benefits such as synaptic plasticity, metabolic pathways and inflamamtory components of AD. Consequently, in a research study by Li D. et al. (2025), suggested that targeting zinc transporter expression and function may provide multifaceted benefits, including regulation of intracellular zinc homeostasis and attenuation of oxidative stress, which are closely linked to synaptic, metabolic and inflammatory processes in AD.
3 Mechanisms of zinc dysregulation in AD
The homeostasis of zinc in the brain is associated with the coordinating system, as under physiological conditions, zinc participates in neurotransmission, enzyme catalysis and gene regulation without causing toxicity (; Chen et al., 2024). Additionally, the disruption in the zinc causes the zinc redistribution across the cellular compartments in the AD condition. The mislocalisation of zinc, which is a characteristic of excess and deficiency of zinc, causes the abnormal accumulation in the extracellular plaques (Zhang et al., 2022; Pavić Vulinović et al., 2026). Hence, the multifactorial network formation due to an imbalance in zinc accelerates the neurodegeneration (D’alessandro et al., 2025). Sikora and Ouagazzal (2021) suggested that at substantial levels, the brain zinc exists in synaptic vesicles of glutamatergic neurons, particularly in the hippocampal mossy fibres; during neuronal activity, the vesicular zinc is co-released with glutamate into the synaptic cleft from the neuron, and it modulates receptor activity and intracellular signalling. Consequently, in AD, the altered synaptic activity and transporter dysfunction lead to excessive zinc release and impaired reuptake (). The aberrant calcium influx and excitotoxic stress are a result of dysregulation of glutamate receptor which increases extracellular zinc, especially NMDA and AMPA receptors. These prolonged excitotoxicity damages dendritic spines and initiates apoptotic signalling cascades, which in turn affects the synaptic plasticity (). Simultaneously, a reduction in intracellular zinc weakens the antioxidant defences and transcriptional regulation (Schoofs et al., 2024). Niu et al. (2020) suggested that the loss of the vesicular zinc transporter ZnT3 in ageing and AD brain might correlate with evidence of cognitive decline, as the reduced ZnT3 expression alters synaptic zinc packaging, contributing to impaired learning and memory. The long-term potentiation in the presence of zinc and synaptic remodelling leads to dysregulation affecting the neural circuits underlying cognition (Harris et al., 2020). Also, the rapid aggregation and enhanced plaque deposition of the Aβ influences the high levels of zinc as these zinc ions bind to the histidine residues within the Aβ, which stabilise oligomeric and fibrillar conformation (Radko et al., 2020; Kechko et al., 2023). Wu et al. (2024) also suggested that zinc-mediated aggregation is not merely a passive process; it alters the biochemical properties of Aβ; hence, the zinc-bound oligomers display an increased resistance to proteolytic degradation and enhanced neurotoxicity. Additionally, these zinc ions can shift the Aβ balance towards the insoluble forms, which reduces the clearance efficiency and accelerates the plaque growth (). Mitkevich et al. (2023) also reported that zinc chelation displayed the partial reversal of plaque formation in animal models, which highlighted the role of zinc in amyloid pathology. Also, the excessive chealtion leads to disrupted physiological zinc-dependent processes, which emphasises the need for the targeted modulation rather than global depletion ().
In a healthy neuron, Tau protein stabilises the microtubules, which support the axonal transport as well as the structural integrity (Barbier et al., 2019), but in AD, the Tau hyperphosphorylated, which makes it detach from microtubules and aggregate into NFTs. The zinc indirectly regulates the kinases and phosphatases that control Tau phosphorylation (Tangavelou and Bhaskar, 2024). Zinc modulates the central regulators of Tau modification, such as cyclin-dependent kinase 5 (CDK5), glycogen synthase kinase-3β (GSK-3β) and protein phosphatase 2A (PP2A) (Zhang et al., 2022). At the molecular level, elevated zinc concentrations disrupt the PI3K/Akt signalling pathway, leading to reduced Akt activity and subsequent disinhibition of GSK-3β, a key kinase responsible for Tau hyperphosphorylation (Cai Z. et al., 2025). Concurrently, zinc can inhibit protein phosphatase 2A (PP2A), further preventing dephosphorylation of Tau (Zhang et al., 2022). This dual modulation, enhancing kinase activity while suppressing phosphatase function, creates a phosphorylation imbalance that promotes Tau aggregation and neurofibrillary tangle formation (Shi and Zhao, 2024). The Tau aggregation stabilises due to increased zinc, which inhibits the phosphatase function while enhancing kinase activity, which causes the hyperphosphorylation (Minckley et al., 2021). The neural network has a spread of Tau pathology, which increases the zinc ion, resulting in cytoskeletal instability, which in turn disrupts axonal transport and eventually leads to synaptic failure and neuronal degeneration (Jiang et al., 2025).
Similarly, due to the increased ROS, the zinc-binding sites, which are essential for the functioning of the antioxidant enzymes, are compromised (Briassoulis et al., 2023). Additionally, the intracellular zinc deficiency impairs enzyme folding and catalytic efficiency, which reduces ROS scavenging capacity (Ionescu-Tucker and Cotman, 2021). Marreiro et al. (2017), conversely, suggested that excess free zinc can itself generate oxidative stress by disrupting mitochondrial electron transport and promoting reactive species formation, and hence the zinc-induced mitochondrial dysfunction leads to decreased ATP production and activation of apoptotic pathways. Moreover, the redox fluctuations are buffered by metallothioneins by exchanging zinc in response to oxidative signals, but in AD, the sustained oxidative stress in the buffering system releases zinc from metallothionein complexes, this creats a feedback loop which self-reinforces the cycle of zinc release and oxidative damage that accelerates neuronal injury (Krezel and Maret, 2021). The excess zinc accumulation within mitochondria interferes with the respiratory chain enzymes, which leads to impairment of the membrane potential and triggers the permeability transition pore opening; this leads to cytochrome c release and activation of caspase-dependent apoptosis (Liu et al., 2021).
In AD neurons, the reduced glucose metabolism and impaired oxidative phosphorylation limit the neuronal resilience under stress as shown in Figure 1, and the zinc dysregulation compounds these deficits by destabilising mitochondrial proteins and disrupting calcium homeostasis (Yuan et al., 2024). The mitochondrial ATP produces the synaptic transmission, and neurons rely heavily on it, and energy collapse directly contributes to cognitive decline (Guo et al., 2017). Moreover, the mitochondrial dysfunction increases ROS production, which loops back into the oxidative stress pathways; hence, the convergence of the zinc toxicity and mitochondrial failure thus represents a critical axis of neurodegeneration (Lu et al., 2025). Garland et al. (2022) suggested that zinc signalling influences immune cell behaviour, cytokine production and inflammatory gene expression, and the abnormal zinc distribution enhances the pro-inflammatory signalling while impairing the protective immune responses. The activated microglia release the zinc into the extracellular space, and potentially, it exacerbates amyloid aggregation and neuronal toxicity (Shippy et al., 2024). The imbalance of the intracellular zinc promotes an inflammatory environment, which weakens the anti-inflammatory pathways and antioxidant defences; this damages synapses and accelerates neuronal loss (Schulz and Rink, 2025). Also, the linkage between the metal homeostasis and inflammatory pathways involves the zinc-binding transcriptional factors, which regulate genes involved in immune modulation; hence, this overlap is usually observed in the AD brain with chronic neuroinflammation (Sauer et al., 2022). Significantly, the effective therapeutic strategies include targeting the nodes of the zinc network as it is largely involved in the structural, enzymatic and transcriptional processes, restoring homeostasis, which may mitigate the amyloid toxicity, Tau pathology and oxidative stress (Lei et al., 2021; Pavić Vulinović et al., 2026). As shown in Table 2.
FIGURE 1
TABLE 2
| Mechanism | Mechanistic insight | Key finding | Relevance to AD | References |
|---|---|---|---|---|
| Synaptic zinc transport | Reduced vesicular Zn2+ impairs synaptic plasticity and neurotransmission | ZnT3 loss leads to age-dependent cognitive decline | Early synaptic dysfunction | ; Choi S. et al., 2020; Vogler et al., 2023 |
| Amyloid aggregation | Zn binds Aβ and accelerates aggregation in plaques | Elevated synaptic Zn promotes amyloid-beta deposition | Plaque formation | Lee et al., 2002; Stoltenberg et al., 2007; Deshpande et al., 2009; Hosseinpour Mashkani et al., 2023; Hosseinpour Mashkani et al., 2024 |
| Metal chelation | Disrupts Zn–Aβ interaction and promotes plaque clearance | Clioquinol reduces amyloid burden | Therapeutic potential | Gouras and Beal, 2001; Wang et al., 2012; Takeda et al., 2017 |
| Metal dyshomeostasis | Increased extracellular Zn enhances Aβ aggregation and toxicity | Excess Zn exacerbates cognitive deficits | Disease progression | Flinn et al., 2005; Corona et al., 2010; Yang et al., 2013; Contestabile et al., 2016; Piechal et al., 2016 |
| Metal-protein interaction | Histidine residues coordinate Zn2+ binding | Zn induces rapid Aβ oligomerization | Toxic oligomer formation | Chen et al., 2011; Lee et al., 2018; Cansız et al., 2025 |
| Tau aggregation | Direct binding alters Tau conformation | Zn promotes Tau aggregation | Neurofibrillary tangle formation | Hu et al., 2017; Li et al., 2019; Moreira et al., 2019; Rocca et al., 2021 |
| Aβ degradation | Excess Zn inhibits proteolytic degradation of Aβ | Zn modulates neprilysin and IDE activity | Reduced Aβ clearance | Strozyk et al., 2009; Sahoo et al., 2021 |
| Oxidative stress | Mitochondrial dysfunction and redox imbalance | Zn accumulation induces ROS production | Neuronal damage | Clausen et al., 2013; Zhao et al., 2018; Pan et al., 2019 |
| Zinc buffering | Loss of intracellular Zn sequestration | MT-3 downregulation increases free Zn2+ | Oxidative stress, toxicity | Lee et al., 2003; Koh and Lee, 2020 |
| Neuroinflammation | Zn-mediated signaling enhances inflammatory cytokines | Zn alters microglial activation | Neuroinflammatory response | Kauppinen et al., 2008; Knoch et al., 2008; Higashi et al., 2017; Li D. et al., 2025 |
| Tau phosphorylation | Kinase/phosphatase imbalance drives abnormal Tau protein phosphorylation | Zn regulates GSK-3β and PP2A | Tau pathology | ; Sun et al., 2012; Xiong et al., 2013 |
| Metal accumulation | Disrupted transcription of neuronal survival genes | Elevated Zn levels in amyloid plaques | Confirms pathological relevance | Suh et al., 2000; Religa et al., 2006; Szabo et al., 2016; Kechko et al., 2023 |
| Metal modulation | Zn co-localizes with Aβ deposits | Chelation therapy shows cognitive stabilization | Translational relevance | Liu et al., 2009; |
Mechanistic roles of zinc dysregulation in the pathogenesis of Alzheimer’s disease.
4 Therapeutic implications
The development of therapeutic strategies aimed at restoring the metal balance while preserving physiological zinc functions is the recent focus in AD research (Li et al., 2022). These approaches fall into three major categories: small-molecule metal modulators, natural compounds with zinc-regulatory potential and gene-based approaches that can modify the zinc-binding proteins. Squitti et al. (2020) suggested that small-molecule metal modulators were among the first pharmacological tools which regulated the zinc balance in AD, specifically focused on the redistribution of zinc from the toxic extracellular aggregated form and restoring intracellular availability. Also, in a study by Zhou X. et al. (2026), reported that 1-Zn is a multifunctional compound which has the potential to restore metal homeostasis by chelating excess Cu2+ and releasing Zn2+, which in turn also reduces oxidative stress, inhibits Aβ aggregation and improves cholinergic function, highlighting its therapeutic potential in AD. The development of the metal-protein attenuating compounds (MPACs) follows the same concept, wherein the MPACs selectively interfere with pathological metal-protein interaction (Khan et al., 2024). Additionally, compounds like PBT2 display strong brain uptake and binding to AD tissues, which highlights its significance in the diagnostic as well as therapeutic potential; the complementary structural and spectroscopic studies on related metal-chelating compounds further support their stability and interaction capabilities, reinforcing their relevance in targeting metal-associated neurotoxicity (de Freitas et al., 2013; Krishnan et al., 2018). Katsoulaki et al. (2025) reported that clioquinol, which is a hydroxyquinoline derivative, is a zinc and copper chelator which can cross the BBB, capable of reducing the amyloid plaque and improving cognitive performance in animal models. Consequently, reported that a dual chelator cocktail targeting both Cu2+ and Zn2+ effectively inhibits ROS generation from Cu-Aβ complexes, as well as the simultaneous and selective modulation of metalmions, which can reduce oxidative stress and offer a promising therapeutic strategy for AD. In contrast to this, Harbison-Price et al. (2020) reported that increased metal chelation risks impairing essential enzymatic processes; hence, the PBT2, an MPCA derived from clioquinol, was designed to improve safety and efficacy. Katsuyama et al. (2021) also suggested that PBT2 functions as a zinc ionophore, which redistributes the zinc into neurons and also facilitates synaptic repair. Unlike the synthetic chelators, the natural compounds often act as multifunctional modulators that affect the redox balance, enzyme activity and gene expression (Lee et al., 2023). A critical challenge in zinc-targeted therapy lies in balancing zinc chelation and zinc ionophore strategies. While chelators aim to reduce excess extracellular zinc and prevent amyloid aggregation, excessive chelation may disrupt essential zinc-dependent enzymatic and transcriptional processes (Gucký and Hamuľaková, 2024). In contrast, zinc ionophores facilitate the redistribution of zinc into intracellular compartments, potentially restoring synaptic function and neuronal signalling. However, uncontrolled intracellular zinc accumulation may also induce toxicity (Kocyła et al., 2021). Therefore, future therapeutic approaches must focus on precise modulation of zinc homeostasis rather than global zinc depletion or indiscriminate redistribution (Das et al., 2025). The zinc dysregulation is also regulated by gene-based therapeutic strategies, where the modification of the zinc-binding proteins and transporters is the target site (Brito et al., 2020). The recent advances in gene editing, which include RNA interference and epigenetic modulation, have opened new possibilities for targeting metal homeostasis at the transcriptional level. As reported in a study by Zhou Y. et al. (2026), the upregulation of ZnT3 might restore vesicular zinc families. Conversely, the downregulation of transporters may also promote the pathological zinc accumulation, which may reduce extracellular toxicity (Sun et al., 2022; Mashkani et al., 2025). Yang et al. (2024) suggested that enhancing the expression of zinc-binding proteins may also increase neuronal resilience, and the gene therapy approaches, which are aimed at boosting metallothionein levels, have demonstrated antioxidant and anti-inflammatory benefits in preclinical studies (Shippy and Ulland, 2022; Mohammed et al., 2025). Similarly, the regulation of zinc-dependent transcription factors could stabilise the disrupted gene regulation in AD (Goel and Saraogi, 2025). Additionally, the siRNAs and antisense oligonucleotides can selectively silence genes that exacerbate zinc-related toxicity, which will allow fine control of gene expression without genomic alteration on a large scale (Kang et al., 2023). Hence, the gene-based interventions may provide the zinc imbalance in vulnerable brain regions, while the gene therapy remains in early stages for neurodegenerative disease, its potential to reprogram zinc ion pathways represents a transformative frontier (Chen et al., 2024).
5 Conclusion
Zinc-binding proteins play a pivotal role in the molecular landscape of AD as they are closely connected with metal homeostasis, which is interconnected with amyloid aggregation, Tau pathology, oxidative stress and neuroinflammation. Recent evidence suggests that zinc dysregulation extends beyond a biochemical abnormality, but is a systemic disturbance that reshapes neuronal signalling, transcriptional regulation and metabolic stability. Zinc-dependent enzymes, metallothioneins, transcriptional factors and related families work together to keep neuronal resilience stable; modification in this network results in disruption, which promotes the multiple neurodegenerative cascades that contribute to cognitive impairment. Hence, the therapies focused on the zinc-related pathways may represent a disease-modifying approach instead of symptomatic relief. Research findings focused on metal-modulating small molecules have shown to regulate zinc distribution, which may inhibit amyloid aggregation. Additionally, genetic approaches regulate the zinc transport mechanisms; these findings indicate that bioactive natural molecules with antioxidant and metal binding properties may offer low toxicity, multimodal therapeutic agents capable of re-establishing zinc dysregulation while simultaneously addressing neuronal inflammation and oxidative damage in AD. Future research should focus on developing precision-based strategies that selectively target zinc-binding proteins and transporters, such as MT-3 and ZnT3, rather than employing non-specific zinc modulation. A systems-level understanding of zinc signalling networks may enable the identification of critical regulatory nodes that can be therapeutically targeted to restore neuronal homeostasis. Integrating zinc biology with disease-specific molecular pathways could pave the way for more effective and personalised interventions in Alzheimer’s disease.
Statements
Author contributions
RU: Conceptualization, Data curation, Visualization, Writing – original draft, Writing – review and editing. SK: Writing – original draft, Writing – review and editing. MS: Conceptualization, Investigation, Supervision, Writing – review and editing.
Funding
The author(s) declared that financial support was not received for this work and/or its publication.
Acknowledgments
The authors sincerely acknowledge the Division of Biotechnology, Karunya Institute of Technology and Sciences (Deemed to be University), for providing the necessary facilities and support that enabled the successful completion of this research.
Conflict of interest
The author(s) declared that this work 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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Abbreviations
AD: Alzheimer’s disease; Aβ: Amyloid-beta; APP: Amyloid precursor protein; ATP: Adenosine triphosphate; BBB: Blood-brain barrier; CDK5: Cyclin-dependent kinase 5; CNS: Central nervous system; GC-MS: Gas chromatography-mass spectrometry; GSK-3β: Glycogen synthase kinase 3 beta; IDE: Insulin-degrading enzyme; LTP: Long-term potentiation; MMPs: Matrix metalloproteinases; MPACs: Metal-protein attenuating compounds; mRNA: Messenger RNA; NFTs: Neurofibrillary tangles; NMDA: N-methyl-D-aspartate; PP2A: Protein phosphatase 2A; ROS: Reactive oxygen species; siRNA: Small interfering RNA; ZnT: Zinc transporter; ZIP: Zrt/Irt-like protein transporter; SLC30: Solute carrier family 30; SLC39: Solute carrier family 39.
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Summary
Keywords
Alzheimer’s disease, amyloid-beta aggregation, metallothioneins, metal-targeted therapy, neurodegeneration, oxidative stress, tau pathology, zinc homeostasis
Citation
Upadhyay R, Kar S and Sevanan M (2026) Zinc-binding proteins in Alzheimer’s disease: mechanisms, therapeutic potential, and natural compound interventions. Front. Chem. Biol. 5:1836070. doi: 10.3389/fchbi.2026.1836070
Received
22 March 2026
Revised
28 April 2026
Accepted
18 May 2026
Published
10 June 2026
Volume
5 - 2026
Edited by
Marco Mazzorana, Diamond Light Source, United Kingdom
Reviewed by
Saltuk Bugra Baltaci, Istanbul Medipol University, Türkiye
Robert Dempski, Worcester Polytechnic Institute, United States
Updates
Copyright
© 2026 Upadhyay, Kar and Sevanan.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Murugan Sevanan, micromurugans@gmail.com
† These authors have contributed equally to this work
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