Kuan Teng Tan1
Kok Whye Cheong1
Lai Chun Wong2
Hélène C. Bertrand3
Nurul Huda Abd Karim4
Yie Kie Chong5
May Lee Low1*- 1Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur, Malaysia
- 2Department of Pharmaceutical Chemistry, School of Pharmacy, IMU University, Kuala Lumpur, Malaysia
- 3Laboratoire Chimie Physique et Chimie du Vivant, CPCV UMR8228, Département de Chimie, École Normale Supérieure, PSL University, Sorbonne Université, CNRS, Paris, France
- 4Department of Chemical Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia (UKM), Bangi, Selangor, Malaysia
- 5School of Foundation Studies, Xiamen University Malaysia, Sepang, Selangor, Malaysia
Neurodegenerative diseases (NDD) such as Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) urgently demand novel therapeutics beyond symptomatic relief. Increasing evidence implicates dysregulation of metal ion homeostasis (e.g., iron, copper, zinc) in the pathogenesis of these diseases, contributing to oxidative stress and protein aggregation. Conventional therapies face limitations including poor brain bioavailability and inability to halt disease progression. In response, metal-based strategies are emerging as promising interventions. This mini-review highlights how restoring metal ion balance and leveraging inorganic chemistry can counter neurodegeneration. We discuss recent advances in metal complexes that target pathogenic pathways, metal-organic frameworks (MOFs) as sophisticated drug delivery scaffolds, and metallic nanoparticles engineered to cross the blood-brain barrier (BBB). These approaches offer unique capabilities to modulate disease processes and deliver multi-functional treatments. By exploring the roles of metal ions in neurobiology and surveying cutting-edge metal-containing therapeutics, we underscore the potential of metals in medicine to unlock new avenues for treating NDD.
1 NDD and metal ions: a molecular connection between disease progression and therapy
NDD are a group of disorders characterized by gradual deterioration of nerve cells, leading to degenerative cognitive functions and motor impairments. Some of the main types of NDD include AD (Pantiya et al., 2020; Mittal and Agrawal, 2024; Wei et al., 2025), PD (Pantiya et al., 2020; Mittal and Agrawal, 2024; Wei et al., 2025), HD (Pantiya et al., 2020; Joshi et al., 2025), and ALS (Mittal and Agrawal, 2024; Wei et al., 2025). A rising body of evidence have suggested that these diseases are often caused by abnormal protein accumulation (Sweeney et al., 2017), oxidative stress (Houldsworth, 2023), mitochondrial dysfunction (Joshi et al., 2025), and genetic mutations (Ogonowski et al., 2024). Symptoms commonly include memory loss, movement impairments, and behavioral changes. The incidence of NDD is projected to increase in parallel with rising life expectancy, imposing a substantial economic burden on public healthcare systems. In 2019, the worldwide cost of dementia (including AD) was estimated at approximately USD 1.3 trillion, equivalent to roughly 1.5% of the world’s GDP (Wimo et al., 2023). In 2022, the economic burden of AD in Malaysia was estimated at USD 1.9 billion, accounting for approximately 0.47% of the nation’s GDP (Ong et al., 2025) These enormous figure highlights the substantial economic impact of AD on societies globally and locally.
At present, there is no known cure for NDD, however, available treatments primarily focus on symptom management and decelerating disease progression. Ion imbalance plays a critical role in linking oxidative stress, cellular apoptosis, aging, and the pathogenesis of major health diseases. In addition, the homeostasis of metals, such as iron, copper, zinc and calcium for maintaining normal neurophysiological activity has been well established. As disruptions or dysfunctions in ion channel activity contribute to the disease progression, metal ion homeostasis-related signaling pathways have emerged as potential therapeutic targets for various neurological disorders (Xu et al., 2022; Zhang Y. Y. et al., 2023). Reviews have shown a potential risk of dyshomeostasis of calcium ion could heighten the risk of PD simply by disrupting interactions between subcellular organelles (e.g., endoplasmic reticulum, mitochondria, and lysosomes) (Xu et al., 2022). In addition, dysregulated iron homeostasis leading to abnormal iron accumulation in the brain regions has been correlated with the progression and severity of various NDD such as PD and AD (Maass et al., 2021; Wu D. et al., 2023). Conversely, exposure to cadmium and lead has been linked to an elevated risk of developing ALS (Peters et al., 2021).
Despite progress in current treatment approaches, significant challenges persist, including limited efficacy, adverse side effects, and the inability to halt disease progression. Growing evidence suggests that metal ions hold promise as therapeutic agents, offering innovative strategies to restore metal homeostasis and counteract disease pathology. Addressing these challenges demands ongoing research and innovation to refine metal-based therapeutics, enhance targeted delivery, and improve clinical translation, ultimately paving the way for more effective treatments and improved patient outcomes. This review next examines how metal dysregulation contributes to disease pathology and why current treatments fall short, in order to contextualize new metal-based therapeutic strategies.
2 Unraveling therapeutic pathways: mechanisms of action and the hurdles of current treatments
NDD are driven by complex, multifactorial mechanisms, including oxidative stress, protein misfolding, and neuroinflammation (Wilson et al., 2023). Among these factors, metal dysregulation has emerged as a significant contributor to disease progression, affecting both oxidative balance and protein aggregation in the brain (Pamphlett and Bishop, 2023).
One key consequence of metal dysregulation is the accumulation of metals such as iron, copper, and zinc in specific brain regions, exacerbating neuronal damage. Meta-analyses have linked elevated iron and iron-related proteins to an increased risk of AD (Gong et al., 2023), while similar findings indicate a strong connection between iron accumulation and neurodegeneration (Vellingiri et al., 2022). The pathological effects of excess metal ions are largely mediated by oxidative stress (Chen et al., 2025). Redox-active metals such as iron contribute to the Fenton reaction, producing highly reactive hydroxyl radicals that ultimately result in neuronal death. Recent studies suggest that both iron and copper dysregulation contribute to PD by promoting α-synuclein aggregation through oxidative mechanisms, further accelerating neurodegeneration (Behl et al., 2022).
Beyond oxidative stress, disruptions in metal ion homeostasis influence key proteins involved in NDD. In AD, the toxic aggregation of Amyloid-beta (Aβ) and tau proteins has been linked to abnormal metal binding (Das et al., 2021). The function of metals such as zinc, copper and iron in promoting Aβ aggregation was initially identified in early studies (Zatta et al., 2009) and later confirmed in subsequent investigations (Doroszkiewicz et al., 2023). Recent nuclear magnetic resonance studies have offered detailed insights into the structures and dynamics of metal-Aβ complexes, shedding further light on their involvement in bulk protein aggregation (Abelein et al., 2022; Abelein, 2023).
While neuroinflammation is often considered a consequence of neurodegeneration, emerging evidence suggests it plays a crucial role in disease progression (Zhang W. et al., 2023). However, recent studies indicate that protein misfolding and aggregation may occur independently of neuroinflammation, suggesting that anti-inflammatory therapies alone may not be sufficient to halt disease progression (Matarazzo et al., 2024). This complexity underscores the need for multi-targeted therapeutic strategies.
Although significant research efforts have been made, finding effective disease-modifying therapies for NDD remains challenging. Existing treatments alleviate symptoms but do not prevent disease advancement, resulting in ongoing neurological deterioration (Akhtar et al., 2021). While numerous drug candidates have entered clinical trials, most fail due to issues with efficacy, safety, or drug delivery challenges (Zhang et al., 2024). For example, dalzanemdor, which was investigated for PD, AD, and HD, was discontinued in 2024 after failing to demonstrate significant benefits over placebo (Sage Therapeutics, 2024).
Traditional therapies also offer limited long-term benefits. For instance, levodopa, the gold standard treatment for PD, loses efficacy over time due to disease progression and the development of peripheral resistance (Beckers et al., 2022). Additionally, many available treatments cause adverse effects (Table 1). For instance, over 50% of patients receiving levodopa develop motor complications within 4 years of starting treatment (Warren Olanow et al., 2013).
Table 1. Current treatment for neurodegenerative diseases and their limitations (Borovac, 2016; Hill et al., 2019; Parkinson’s UK, 2025; Medscape, 2025).
One of the greatest obstacles in NDD treatment is the BBB, a highly selective membrane that restricts the entry of most therapeutic molecules into the central nervous system (CNS) (Zlokovic, 2008; Wu D. et al., 2023). Since NDD involve progressive brain deterioration, effective treatments must cross the BBB to reach target sites. However, poor bioavailability in the CNS remains a critical limitation in delivering successful treatments (Akhtar et al., 2021). The next section explores such metal-based therapeutic avenues.
3 Translating metal-based therapeutics: applications across preclinical and clinical studies
3.1 Metal complexes in neurodegeneration: therapeutic roles in AD and PD
In light of the above challenges, researchers are exploring various metal-based compounds that target common pathological features like protein aggregation and metal ion imbalance.
Because of the critical roles of copper, zinc and iron accumulation in NDD, metal chelators have received considerable attention. For more detail on this approach, readers are referred to recent reviews (Sales et al., 2019; Vilella et al., 2020; Fasae et al., 2021; Du et al., 2024; Liu et al., 2024). Chelators, through binding to metal ions, prevent them from generating oxidative stress and from interacting with amyloid proteins, in turn inhibiting aggregation. In the context of NDD, a new class of chelators, characterized by a weaker affinity, named metal protein attenuating compounds (MPACs) are developed. MPACs are designed to cross the BBB and to remove excess accumulated metal ions (Zn2+ and Cu2+) without disrupting bulk metal coordination and normal functioning of metalloenzymes and related biological processes. Following promising outcomes from preclinical studies in AD and PD models respectively, the 8-hydroxyquinoline derivatives PBT2 (Faux et al., 2010; Huntington Study Group Reach2HD Investigators, 2015; Villemagne et al., 2017) and PBT434 (Stamler et al., 2020; Levi and Volonté, 2023) have reached clinical trials (phase II in AD and HD patients and phase I respectively) (Figure 1). Similarly, Desferrioxamine (DFO), a chelator for trivalent ions (Figure 1) successfully entered AD phase II clinical trials, and, however, was discontinued due to the poor BBB penetration and systemic toxicity at high dosages.
Figure 1. Structures of chelators and metal complexes.
Lithium-based treatments, which have long been used to treat psychiatric disorders (Cade, 1949), have been proposed to provide neuroprotection in neurodegenerative contexts (AD and PD, for example,) in in vivo studies (Lovestone et al., 1999; Alvarez et al., 2002; Su et al., 2004; Noble et al., 2005; Engel et al., 2006; Engel et al., 2008; Macdonald et al., 2008; Fiorentini et al., 2010; Leroy et al., 2010; Quiroz et al., 2010; Zhang et al., 2011; Forlenza et al., 2014; Lazzara and Kim, 2015; Gao et al., 2022) and were evaluated in a few clinical trials (Hampel et al., 2009; Forlenza et al., 2011).
Metallodrugs are also actively developed for the treatment of NDD, with diverse modes of action (MOA). The latest developments are described in several recent reviews (Liu et al., 2024; Florio et al., 2025). Most of those studied so far target Aβ species with the aim of inhibiting aggregation by interfering with the protein-metal ions interactions. Their interaction with such species, which can include coordination of protein side chains, can alter amyloid protein structures and aggregation states or stabilize non-toxic conformations. Antioxidant properties or inhibition of acetylcholinesterase are alternative modes of action.
Metal complexes evaluated in this context comprise platinum, ruthenium, iridium, gold, cobalt, vanadium, manganese/iron, copper and zinc complexes along with homo- and hetero-bimetallic species (Table 2). Promising results were obtained in vitro and in cellular models. However, few have been evaluated in vivo, often due to BBB crossing challenges.
Table 2. Metal complexes assessed for neurodegenerative diseases.
A Pt (II) complex of a functionalized 8-BQ ligand (8-(1H-benzoimidazol-2-yl)-quinoline), 1, was developed and demonstrated a reduction of Aβ toxicity in primary mouse cortical neuronal cell cultures (Kenche et al., 2013). The Pt (IV) corresponding prodrug, 2, showed higher Pt levels in the brain of wild type mice compared to the Pt (II) complex (Figure 1). In a mouse model of AD (APP/PS1), a reduction in Aβ42 levels and in plaque number was observed in the Pt (IV) treated group (Kenche et al., 2013). More recently, Co(III)-salnaph complexes showing Aβ aggregation inhibition properties (3-4), were delivered across BBB in mice (C57BL/6J and transgenic 5xFAD mice as AD model) by use of focused ultrasound and was shown to be well-tolerated (Figure 1) (Chan et al., 2021). Zinc complexes such as pine peptide–zinc chelates (Zhang Z. et al., 2023) and Zn(II)-based amide carboxylate (Waseem et al., 2022) were shown to have potential in AD treatment with improvements in memory and learning in AD murine models through reduction in acetylcholinesterase levels and antioxidant properties among others. Finally, the thiosemicarbazone-pyridylhydrazone Cu(II) complex CuL5 (Figure 1) demonstrated cognitive benefits despite increasing amyloid plaques in treated in 5xFAD mice (Choo et al., 2022).
Despite extensive research, few metal chelators or metal-based drugs have been evaluated in vivo so far. Further efforts are needed to translate promising in vitro results into preclinical and clinical evaluations to confirm their potential in reducing neurotoxicity in the treatment of NDD. To this aim, key chemical properties of the drug candidates such as pharmacokinetics require optimisation to limit toxicity and enhance BBB crossing ability.
3.2 Therapeutic potentials of MOFs: controlled drug release and metal ion homeostasis
Latterly, MOFs have garnered remarkable attention in biomedical applications. These materials composed of metals ions extensively coordinated with organic ligands are characterized with high crystallinity, porosity, and versatility for structural modification. Examples of well-established MOFs include MIL-100(Fe), ML-101(Cr), UiO-66, ZIF-8 etc. (Abánades Lázaro et al., 2024; Wang et al., 2024). Henceforth, MOFs have been prevalently investigated for their potential in drug delivery and metal ion regulation.
Harnessing MOFs as drug delivery system (DDS) generates merits including enhanced biocompatibility, controlled-release, stability, and targeting effect (Wang et al., 2024). Recently, encapsulation of hydrophobic quercetin within zeolitic imidazolate MOFs with Prussian blue coating (ZIF-8@PB-QCT) was designed for PD therapy. Intriguingly, functionalization with PB permits heat-stimulated release of QCT upon photoirradiation in near infrared region, improving penetration across BBB, hence uptake by neuronal cells. Ultimately, non-invasive delivery of ZIF-8@PB-QCT exerted protective effects against neurotoxins and mitochondrial damage, subsequently ameliorated locomotive ability of impaired mice (Liu et al., 2021). Likewise, ZIF-8 framework loaded with Kaempferol and bearing polydopamine coating was synthesized for Postoperative Neurocognitive Disorder treatment. Evidently, anti-inflammatory and anti-oxidative effects were prominent during in vivo studies, with improvement in hippocampal neuron viability and cognitive function (Huang et al., 2024). Furthermore, a cyclodextrin-based MOFs modified with stigmasterol and lactoferrin was formulated for huperzine A delivery in AD treatment. The framework was dispersed in a hyaluronic acid/gelatin-tannic acid microneedle patch, subsequently delivered via nasal route. Inclusion of lactoferrin improved targeting for intracerebral uptake while modified patch reduced aqueous degradation and toxicity. Impressively, microneedle-assisted MOFs delivery enhanced BBB penetration and accumulation of huperzine A, concurrently reducing clearance by nasal cilia. Overall, inhibition of neuronal oxidative damage and restoration of impaired mice’s neurological function was achieved (Ruan et al., 2024).
Intriguingly, biodegradation of MOFs has been optimized to stimulate controlled release of metal ions to cure deficiency. An investigation on MOF-74(Cu) elucidated the copper-release kinetics, shedding light on potential treatment against copper deficient neurological diseases including ALS and PD. Remarkably, zero-order controlled release of copper promoted brain accumulation, simultaneously minimizing liver intoxication for replenishment of body essential elements (Aguila-Rosas et al., 2024). Another study focused on alleviation of spinal cord injury (SCI) via exploiting ZIF-8 framework to induce neurodifferentiation of dental pulp stem cells (DPSCs), replenish Zn2+ levels, and trigger angiogenesis. Distinctly, combinatorial treatment with ZIF-8-DPSCs healed impaired neurons and rectified the locomotive ability of rats with SCI (Zhou et al., 2023).
In contrast, excessive accumulation of metal ions promotes the conformational change of Aβ peptides into aggregates, resulting in deterioration of neurological function and triggering the onset of AD (Abelein, 2023). In efforts to ameliorate AD, varying porphyrin-modified MOFs (PMOFs) were formulated to facilitate the removal of excessive copper (II) ions to restrict Aβ aggregation and neurotoxicity. In particular, Hafnium-based PMOFs demonstrated significant copper (II) chelation and singlet oxygen generation capacity upon photoirradiation at 450 nm. Evidently, treatment of Hf-PMOFs on AD transgenic roundworms rectified the locomotive ability, diminished paralysis and prolonged the lifespan (Yu et al., 2019).
3.3 Crossing the barrier: metallic nanoparticles in targeted CNS drug delivery
The treatment of NDD presents significant therapeutic challenges, primarily due to the formidable BBB. BBB is a highly selective semipermeable border of endothelial cells that protects the brain from harmful substances. It also simultaneously limits the entry of many potential therapeutics to the CNS, thus hindering its drug delivery effectiveness (Teleanu et al., 2018; Niu et al., 2019). Since the BBB restricts systemically administered compounds’ access to the brain, large drug doses are required every time, unfortunately causing toxic effects (González-Domínguez et al., 2014).
Recent advancements in nanotechnology have introduced metal nanoparticles (MNPs) as promising vehicles for targeted drug delivery across the BBB, offering new avenues for NDD treatment (Sintov et al., 2016; Furtado et al., 2018; Abidi et al., 2023). The latest advances are thoroughly discussed in several recent reviews. These nanoparticles, including gold (Chang et al., 2021), silver (Qin et al., 2025), and iron oxide, exhibit unique physicochemical properties such as small size and large surface area. The desirable feature of metallic nanoparticles also includes the ability to be functionalized for a specific target. The ability to deliver drugs directly to the brain is enhanced, it improves bioavailability, and reduces side effects (Li et al., 2021; Scarpa et al., 2023).
Altering the size, shape, and surface chemistry of these nanoparticles can impact their participation in various transport mechanisms, such as receptor-mediated transcytosis and adsorptive-mediated transcytosis, in turn helping them cross the BBB. Due to their nontoxic features, gold nanoparticles have been highlighted for their multifunctional capabilities, including the ability to undergo surface modifications and target specific brain regions (Chang et al., 2021; Silveira et al., 2021; Puranik et al., 2023; McLoughlin et al., 2024; Roghani et al., 2024). To improve drug delivery efficiency, these modifications can include functionalization with targeting ligands (Zhao et al., 2022; Roghani et al., 2024). For example, insulin-targeted gold nanoparticles (INS-GNPs) have been demonstrated to effectively cross the BBB, resulting in significant accumulation in the brain. Such results show the potential of INS-GNP as a delivery system for NDD treatments (Shilo et al., 2014; Betzer et al., 2019). INS-GNP demonstrated an accumulation exceeding five times that of untargeted gold nanoparticles by targeting insulin receptors.
The precision of drug delivery in AD and PD has also been proved by the functionalization of AuNP to specifically target pathological proteins such as Tau and α-synuclein (Tapia-Arellano et al., 2024). Silver nanoparticles (AgNPs) have been shown to enhance BBB permeability (Li et al., 2021). The interaction with endothelial cells modulates the expression of proteins that relate to oxidative stress and neurodegeneration (López-Espinosa et al., 2024). They have been shown to upregulate the proteins associated neurodisorders and downregulates those that sustain brain homeostasis. Consequently, AgNPs may facilitate drug delivery while potentially inducing neurotoxicity (Khan et al., 2019). Despite these concerns, their antimicrobial and anticancer properties make them promising for neurogenesis disease theragnostic (combining therapeutic and diagnostic capabilities) (Teixeira et al., 2025). Similar to AuNPs, AgNPs can also be designed to target specific molecular pathways involved in neurodegeneration (Ribeiro et al., 2022). The general goal is to improve their therapeutic potential while reducing adverse effects (Mistretta et al., 2023; López-Espinosa et al., 2024; Qin et al., 2025).
Other metal nanoparticles, such as those based on iron, copper or zinc (Jaragh-Alhadad and Falahati, 2022), have been investigated for their magnetic characteristics. The presence of an external magnetic field makes it possible to guide the magnetic nanoparticles to specific brain areas (McLoughlin et al., 2024; Toader et al., 2024). These nanoparticles can be designed to be able to release drugs in a controlled manner (Kalaiselvi et al., 2020; Mendake et al., 2024). The potential of cerium nanoparticles in addressing treatment challenges associated with AD has also been explored (Hanzha et al., 2023). The brain-targeted nanoparticle, Ce/Zr-MOF@Cur-Lf, has been synthesized and described to improve drug transport across the BBB. Curcumin-loaded Ce/Zr-MOF@Cur-Lf can mitigate oxidative stress, a significant contributor to NDD (Yang et al., 2024).
Despite these advantages, the requirement for thorough safety and the scalability of the metallic nanoparticles production for clinical application need to be addressed (Rafati et al., 2024; Rehman et al., 2024). Overall, the integration of nanotechnology in NDD treatment holds significant promise since it offers innovative solutions to overcome the limitations posed by the BBB (Riccardi et al., 2021; Mistretta et al., 2023).
3.4 Exploring protein aggregation and metal imbalance in NDD using metallopeptides
Metallopeptides have been widely used to study and understand the underlying molecular mechanism that govern protein misfolding and metal homeostasis in the CNS. Studies have shown that the presence of metal ions tends to block the enzymes that break down Aβ and creates harmful free radicals which induce peptide conformation changes and lead to Aβ aggregation (Lovell et al., 1998; Dong et al., 2003; Miller et al., 2006; Tamano and Takeda, 2015). A recent NMR study revealed that metal-Aβ complexes inhibit fibril formation at low metal ion concentrations but promote amorphous aggregation at higher concentrations (Abelein, 2023). Several studies focus on using metal chelators, such as the amino-terminal copper and nickel binding site (ATCUN) to remove excess metal ions and regulate metal homeostasis to prevent Aβ aggregation, as illustrated in Figure 2a. Mital et al. examined how copper and zinc bind to the ATCUN motif that derived from Aβ(12–16) to better understand its coordination with metal ions (Mital et al., 2020). This study demonstrated that the 3N copper-peptide complex (Figure 2b) formed at low pH to a more stable 4N complex (Figure 2c) at pH above pH 6 monitored using UV-Vis and CD spectroscopy. Most of the copper-peptide complex formed at pH 7.4. Besides, Lefèvre et al. has also studied the sequence of ATCUN peptide in relation to its reactive oxygen species (ROS) activity in AD and found that all the eight synthesized ATCUN peptides formed the same thermodynamic complex with Cu(II) (Lefèvre et al., 2022). The addition of histidine at position 1 or 2 improved copper uptake kinetics and the ability to prevent ROS formation, especially with motifs HWHG and HGHW.
Figure 2. (a) Metal-ATCUN derivatives to remove excess metal ions and regulate metal homeostasis to prevent Aβ aggregation. (b) Val12 and His13 bind Cu2+ with 3N (ATCUN) and (c) Val12, His13 and His14 bind Cu2+ with 4N coordination modes, depending on the pH.
In addition, Pandini et al. revealed that the addition of copper and zinc to nerve growth factor (NGF) and NGF (1–14) enhanced the phosphorylation of CREB, Akt and ERK, which are important signaling molecules involved in cell growth, survival and differentiation, but acetylated NGF (1–14) have no significant effect due to lower copper binding stability compared to NGF (1–14), highlighting the potential of metallopeptide in neurodisorder (Pandini et al., 2016). Russo et al. studied the neurotrophic activity of synthetic peptides based on the first 12 amino acids of BDNF N-terminal (HSDPARRGELSV, m-bdnf) and its dimer linked by a disulphide bridge (HSDPARRGELSVC-CVSLEGRRAPDSH, d-bdnf), focusing on zinc ion modulation (Russo et al., 2022). D-bdnf was found to have activity like BDNF but loses effectiveness in promoting neuron growth when bound to zinc. Under acidic conditions, zinc binding decreases due to histidine protonation. A zinc preference for binding to the terminal histidine residues was also found. Besides, both d-bdnf and m-bdnf coordinated with only one Zn2+ ion despite having two histidine residues might be due to the higher flexibility compared to m-bdnf.
Tachykinins, a family of neuropeptides involved in various physiological and pathological processes, have been shown to possess excellent metal chelation properties with high binding affinity (Steinhoff et al., 2014). Metals such as Cu, Ag, Ni, and Zn have been studied for their binding to tachykinins and neuropeptides, including NKA, NKB, SP, NPG, and NPY (Pettit et al., 1991; Harford and Sarkar, 1997; Pietruszka et al., 2011; Russino et al., 2013; Grosas et al., 2014; Ye et al., 2018; Ben-Shushan et al., 2020; Ben-Shushan and Miller, 2021a; Ben-Shushan and Miller, 2021b). These studies revealed that these tachykinins are potential metal chelators with high metal binding affinity. However, the experimental investigation into their role as metal chelators remains scarce. Recently, molecular modelling studies confirmed that three tachykinins can bind Cu2+ and Zn2+ ions, shedding light on their potential in metal ion interactions (Ben-Shushan et al., 2020).
4 Challenges and future perspectives
Metal-based therapies offer several compelling advantages over conventional approaches. Specificity can be heightened by designing complexes, MOFs or nanocarriers that target pathological hallmarks (for example, stimuli-responsive metal nanoparticles enable target-specific drug release in diseased neurons) (Behera et al., 2023). Such systems are often multifunctional, capable of concurrent therapeutic and diagnostic (theragnostic) roles or combined actions. In addition, pairing metal nanoparticles with chelators or other metal complexes can yield synergistic, multi-pronged effects (Behera et al., 2023). Furthermore, incorporating drugs into metal complexes or nanoscale metal frameworks can improve bioavailability and delivery to the brain.
Nanosystems have been shown to ferry drugs across the BBB more effectively than free small molecules (Mistretta et al., 2023), addressing a major limitation in neurodegenerative treatment. Customizing the surface properties of metallic nanoparticles further enhances their specificity and biocompatibility, as demonstrated with gold nanoparticles achieving targeted, prolonged action with minimal immune response (Chiang et al., 2024).
Despite these advantages, significant challenges remain before metal-based therapeutics can fully realize their potential. Toxicity is a foremost concern with many metal compounds that can induce off-target effects or oxidative damage if not carefully controlled. For instance, certain metal nanoparticles tend to release free metal ions or aggregate in vivo, which may trigger neuroinflammation and neuronal toxicity (Shahalaei et al., 2024). Ensuring stability of these agents under physiological conditions is crucial; premature degradation or uncontrolled metal release can not only reduce efficacy but also heighten side effects.
BBB penetration represents another double-edged sword. While innovative nanoformulations are being designed to cross the BBB, it is challenging to achieve sufficient brain uptake without disrupting the BBB’s integrity or causing systemic issues (Shahalaei et al., 2024). Careful engineering is required so that delivery vehicles transit into the brain parenchyma efficiently yet safely. Moreover, the clinical translation of metal-based drugs is impeded by gaps in understanding their long-term behavior in the brain. For instance, nanoparticles accumulating in neural tissue might have unknown chronic effects (Shahalaei et al., 2024). Rigorous in vivo studies and safety assessments are needed to address these uncertainties.
Looking ahead, research is actively focused on overcoming these hurdles and enhancing the therapeutic promise of metal-based interventions. One key direction is improving biocompatibility: by using biologically friendly coatings or green synthesis methods, scientists aim to produce metal nanoparticles that evade immune detection and minimize toxicity (Chiang et al., 2024). Such surface modifications can also bolster particle stability and circulation time, ensuring the therapeutic payload reaches its target (Tan et al., 2025).
Another future avenue is personalized medicine. Given the patient-to-patient variability in metal metabolism and disease progression, tailoring treatments (for example, dosing of metal chelators or selecting specific metal-based agents) to an individual’s genetic and biochemical profile could maximize efficacy and safety. In parallel, researchers are developing hybrid nanoplatforms that combine metal components with organic or biological molecules to harness the best attributes of each. These hybrids such as metal–polyphenol networks or metal-loaded exosome mimics offer the flexibility to integrate targeting ligands, responsive release mechanisms, and multi-drug payloads in one system, addressing multiple disease pathways simultaneously (Shahalaei et al., 2024).
Finally, the integration of artificial intelligence (AI) is poised to accelerate progress in this field. AI-driven drug discovery platforms can rapidly screen and optimize metal-based compounds, predicting properties like BBB permeability and toxicity before clinical testing (Nehmeh et al., 2024). By expediting the identification of promising metal complexes or nanomaterials and guiding rational design, machine learning tools may significantly shorten the development cycle for next generation neurotherapeutics.
5 Conclusion
In conclusion, metal-centered strategies are expanding the therapeutic toolkit for NDD, offering hope for more effective treatments. By capitalizing on their specificity and multifunctionality while diligently addressing safety and delivery challenges, future research will pave the way for metal-based medicines that can modify disease course. Interdisciplinary efforts uniting chemists, neuroscientists, clinicians, and data scientists will be essential to translate these innovative approaches from bench to bedside, ultimately unlocking new avenues to combat disorders like AD, PD, HD and ALS.
Author contributions
KT: Writing – original draft, Writing – review and editing. KC: Writing – original draft, Writing – review and editing. LW: Writing – original draft, Writing – review and editing. HB: Writing – original draft, Writing – review and editing. NA: Writing – original draft, Writing – review and editing. YC: Writing – original draft, Writing – review and editing. ML: Writing – original draft, Writing – review and editing.
Funding
The author(s) declare that no financial support was received for the research and/or publication of this article.
Acknowledgments
The authors thank UCSI University, IMU University, École Normale Supérieure - PSL University, CNRS, Sorbonne Université and Xiamen University Malaysia for support.
Conflict of interest
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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References
Abánades Lázaro, I., Chen, X., Ding, M., Eskandari, A., Fairen-Jimenez, D., Giménez-Marqués, M., et al. (2024). Metal–organic frameworks for biological applications. Nat. Rev. Methods Prim. 4, 42. doi:10.1038/s43586-024-00320-8
Abelein, A. (2023). Metal binding of Alzheimer’s amyloid-β and its effect on peptide self-assembly. Acc. Chem. Res. 56, 2653–2663. doi:10.1021/acs.accounts.3c00370
Abelein, A., Ciofi-Baffoni, S., Mörman, C., Kumar, R., Giachetti, A., Piccioli, M., et al. (2022). Molecular structure of Cu(II)-bound amyloid-β monomer implicated in inhibition of peptide self-assembly in Alzheimer’s disease. JACS Au 2, 2571–2584. doi:10.1021/jacsau.2c00438
Abidi, S. M. S., Sharma, C., Randhawa, S., Shukla, A. K., and Acharya, A. (2023). A review on nanotechnological perspective of “the amyloid cascade hypothesis” for neurodegenerative diseases. Int. J. Biol. Macromol. 253, 126821. doi:10.1016/j.ijbiomac.2023.126821
Aguila-Rosas, J., García-Martínez, B. A., Ríos, C., Diaz-Ruiz, A., Obeso, J. L., Quirino-Barreda, C. T., et al. (2024). Copper release by MOF-74(Cu): a novel pharmacological alternative to diseases with deficiency of a vital oligoelement. RSC Adv. 14, 855–862. doi:10.1039/D3RA07109J
Akhtar, A., Andleeb, A., Waris, T. S., Bazzar, M., Moradi, A. R., Awan, N. R., et al. (2021). Neurodegenerative diseases and effective drug delivery: a review of challenges and novel therapeutics. J. Control. Release 330, 1152–1167. doi:10.1016/j.jconrel.2020.11.021
Almeida, M. P., Kock, F. V. C., de Jesus, H. C. R., Carlos, R. M., and Venâncio, T. (2021). Probing the acetylcholinesterase inhibitory activity of a novel Ru(II) polypyridyl complex and the supramolecular interaction by (STD)-NMR. J. Inorg. Biochem. 224, 111560. doi:10.1016/j.jinorgbio.2021.111560
Alvarez, G., Muñoz-Montaño, J. R., Satrústegui, J., Avila, J., Bogónez, E., and Díaz-Nido, J. (2002). Regulation of tau phosphorylation and protection against β-amyloid-induced neurodegeneration by lithium. Possible implications for Alzheimer’s disease. Bipolar Disord. 4, 153–165. doi:10.1034/j.1399-5618.2002.01150.x
Batchelor, L. K., Ortiz, D., and Dyson, P. J. (2019). Histidine targeting heterobimetallic ruthenium(II)–gold(I) complexes. Inorg. Chem. 58, 2501–2513. doi:10.1021/acs.inorgchem.8b03069
Beckers, M., Bloem, B. R., and Verbeek, M. M. (2022). Mechanisms of peripheral levodopa resistance in Parkinson’s disease. NPJ Park. Dis. 8, 56. doi:10.1038/s41531-022-00321-y
Behera, A., Sa, N., Pradhan, S. P., Swain, S., and Sahu, P. K. (2023). Metal nanoparticles in Alzheimer’s disease. J. Alzheimer's Dis. Rep. 7, 791–810. doi:10.3233/ADR-220112
Behl, T., Madaan, P., Sehgal, A., Singh, S., Anwer, M. K., Makeen, H. A., et al. (2022). Mechanistic insights expatiating the redox-active-metal-mediated neuronal degeneration in Parkinson’s disease. Int. J. Mol. Sci. 23, 678. doi:10.3390/ijms23020678
Ben-Shushan, S., and Miller, Y. (2021a). Molecular mechanisms and aspects on the role of neuropeptide Y as a Zn2+ and Cu2+ chelator. Inorg. Chem. 60, 484–493. doi:10.1021/acs.inorgchem.0c03350
Ben-Shushan, S., and Miller, Y. (2021b). Neuropeptides: roles and activities as metal chelators in neurodegenerative diseases. J. Phys. Chem. B 125, 2796–2811. doi:10.1021/acs.jpcb.0c11151
Ben-Shushan, S., Hecel, A., Rowinska-Zyrek, M., Kozlowski, H., and Miller, Y. (2020). Zinc binding sites conserved in short neuropeptides containing a diphenylalanine motif. Inorg. Chem. 59, 925–929. doi:10.1021/acs.inorgchem.9b03199
Betzer, O., Shilo, M., Motiei, M., and Popovtzer, R. (2019). “Insulin-coated gold nanoparticles as an effective approach for bypassing the blood-brain barrier,” in Nanoscale imaging, sensing, and actuation for biomedical applications XVI. Editors D. V. Nicolau, D. Fixler, and E. M. Goldys (San Francisco, CA: SPIE), 52. doi:10.1117/12.2510353
Borovac, J. A. (2016). Side effects of a dopamine agonist therapy for Parkinson’s disease: a mini-review of clinical pharmacology. Yale J. Biol. Med. 89, 37–47.
Cade, J. F. J. (1949). Lithium salts in the treatment of psychotic excitement. Med. J. Aust. 2, 349–352. doi:10.5694/j.1326-5377.1949.tb36912.x
Chan, T. G., Ruehl, C. L., Morse, S. V., Simon, M., Rakers, V., Watts, H., et al. (2021). Modulation of amyloid-β aggregation by metal complexes with a dual binding mode and their delivery across the blood–brain barrier using focused ultrasound. Chem. Sci. 12, 9485–9493. doi:10.1039/D1SC02273C
Chang, Y., Cho, B., Lee, E., Kim, J., Yoo, J., Sung, J.-S., et al. (2021). Electromagnetized gold nanoparticles improve neurogenesis and cognition in the aged brain. Biomaterials 278, 121157. doi:10.1016/j.biomaterials.2021.121157
Chen, X., Wang, J., Mo, Z., Han, L., Cheng, K., Xie, C., et al. (2024). Development of Ru-polypyridyl complexes for real-time monitoring of Aβ oligomers and inhibition of Aβ fibril formation. Biomaterials Sci. 12, 1449–1453. doi:10.1039/D3BM01929B
Chen, L., Shen, Q., Liu, Y., Zhang, Y., Sun, L., Ma, X., et al. (2025). Homeostasis and metabolism of iron and other metal ions in neurodegenerative diseases. Signal Transduct. Target. Ther. 10, 31. doi:10.1038/s41392-024-02071-0
Chiang, M.-C., Yang, Y.-P., Nicol, C. J. B., and Wang, C.-J. (2024). Gold nanoparticles in neurological diseases: a review of neuroprotection. Int. J. Mol. Sci. 25, 2360. doi:10.3390/ijms25042360
Choo, X. Y., McInnes, L. E., Grubman, A., Wasielewska, J. M., Belaya, I., Burrows, E., et al. (2022). Novel anti-neuroinflammatory properties of a thiosemicarbazone–pyridylhydrazone copper(II) complex. Int. J. Mol. Sci. 23, 10722. doi:10.3390/ijms231810722
Cuccioloni, M., Cecarini, V., Bonfili, L., Pettinari, R., Tombesi, A., Pagliaricci, N., et al. (2022). Enhancing the amyloid-β anti-aggregation properties of curcumin via arene-ruthenium(ii) derivatization. Int. J. Mol. Sci. 23, 8710. doi:10.3390/ijms23158710
da Silva, W. M. B., Pinheiro, S. D. O., Alves, D. R., de Menezes, J. E. S. A., Magalhães, F. E. A., Silva, F. C. O., et al. (2021). Anacardic acid complexes as possible agents against Alzheimer’s disease through their antioxidant, in vitro, and in silico anticholinesterase and ansiolic actions. Neurotox. Res. 39, 467–476. doi:10.1007/s12640-020-00306-w
Das, N., Raymick, J., and Sarkar, S. (2021). Role of metals in Alzheimer’s disease. Metab. Brain Dis. 36, 1627–1639. doi:10.1007/s11011-021-00765-w
Dong, J., Atwood, C. S., Anderson, V. E., Siedlak, S. L., Smith, M. A., Perry, G., et al. (2003). Metal binding and oxidation of amyloid-β within isolated senile plaque cores: raman microscopic evidence. Biochemistry 42, 2768–2773. doi:10.1021/bi0272151
Dong, Y., Stewart, T., Zhang, Y., Shi, M., Tan, C., Li, X., et al. (2019). Anti-diabetic vanadyl complexes reduced Alzheimer’s disease pathology independent of amyloid plaque deposition. Sci. China Life Sci. 62, 126–139. doi:10.1007/s11427-018-9350-1
Doroszkiewicz, J., Farhan, J. A., Mroczko, J., Winkel, I., Perkowski, M., and Mroczko, B. (2023). Common and trace metals in Alzheimer’s and Parkinson’s diseases. Int. J. Mol. Sci. 24, 15721. doi:10.3390/ijms242115721
Drzeżdżon, J., Pawlak, M., Matyka, N., Sikorski, A., Gawdzik, B., and Jacewicz, D. (2021). Relationship between antioxidant activity and ligand basicity in the dipicolinate series of oxovanadium(iv) and dioxovanadium(v) complexes. Int. J. Mol. Sci. 22, 9886. doi:10.3390/ijms22189886
Du, B., Chen, K., Wang, W., and Lei, P. (2024). Targeting metals in Alzheimer’s disease: an update. J. Alzheimer's Dis. 101, S141–S154. doi:10.3233/JAD-240140
Ehlbeck, J. T., Grimard, D. M., Hacker, R. M., Garcia, J. A., Wall, B. J., Bothwell, P. J., et al. (2024). Finding the best location: improving the anti-amyloid ability of ruthenium(III) complexes with pyridine ligands. J. Inorg. Biochem. 250, 112424. doi:10.1016/j.jinorgbio.2023.112424
Engel, T., Goñi-Oliver, P., Lucas, J. J., Avila, J., and Hernández, F. (2006). Chronic lithium administration to FTDP-17 tau and GSK-3β overexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation, but pre-formed neurofibrillary tangles do not revert. J. Neurochem. 99, 1445–1455. doi:10.1111/j.1471-4159.2006.04139.x
Engel, T., Goñi-Oliver, P., Gómez de Barreda, E., Lucas, J. J., Hernández, F., and Avila, J. (2008). Lithium, a potential protective drug in Alzheimer’s disease. Neurodegener. Dis. 5, 247–249. doi:10.1159/000113715
Fasae, K. D., Abolaji, A. O., Faloye, T. R., Odunsi, A. Y., Oyetayo, B. O., Enya, J. I., et al. (2021). Metallobiology and therapeutic chelation of biometals (copper, zinc and iron) in Alzheimer’s disease: limitations, and current and future perspectives. J. Trace Elem. Med. Biol. 67, 126779. doi:10.1016/j.jtemb.2021.126779
Faux, N. G., Ritchie, C. W., Gunn, A., Rembach, A., Tsatsanis, A., Bedo, J., et al. (2010). PBT2 rapidly improves cognition in Alzheimer’s disease: additional phase II analyses. J. Alzheimer's Dis. 20, 509–516. doi:10.3233/JAD-2010-1390
Fiorentini, A., Rosi, M. C., Grossi, C., Luccarini, I., and Casamenti, F. (2010). Lithium improves hippocampal neurogenesis, neuropathology and cognitive functions in APP mutant mice. PLoS One 5, e14382. doi:10.1371/journal.pone.0014382
Florio, D., Iacobucci, I., Ferraro, G., Mansour, A. M., Morelli, G., Monti, M., et al. (2019a). Role of the metal center in the modulation of the aggregation process of amyloid model systems by square planar complexes bearing 2-(2-pyridyl)benzimidazole ligands. Pharmaceuticals 12, 154. doi:10.3390/ph12040154
Florio, D., Malfitano, A. M., Di Somma, S., Mügge, C., Weigand, W., Ferraro, G., et al. (2019b). Platinum(II) O,S complexes inhibit the aggregation of amyloid model systems. Int. J. Mol. Sci. 20, 829. doi:10.3390/ijms20040829
Florio, D., Cuomo, M., Iacobucci, I., Ferraro, G., Mansour, A. M., Monti, M., et al. (2020). Modulation of amyloidogenic peptide aggregation by photoactivatable CO-releasing ruthenium(II) complexes. Pharmaceuticals 13, 171. doi:10.3390/ph13080171
Florio, D., Marasco, D., and Manna, S. L. (2025). Approaches for developing peptide- and metal complexes- or chelators-based leads for anti-amyloid drugs. Inorganica Chim. Acta 577, 122474. doi:10.1016/j.ica.2024.122474
Forlenza, O. V., Diniz, B. S., Radanovic, M., Santos, F. S., Talib, L. L., and Gattaz, W. F. (2011). Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br. J. Psychiatry 198, 351–356. doi:10.1192/bjp.bp.110.080044
Forlenza, O. V., De-Paula, V. J. R., and Diniz, B. S. O. (2014). Neuroprotective effects of lithium: implications for the treatment of Alzheimer’s disease and related neurodegenerative disorders. ACS Chem. Neurosci. 5, 443–450. doi:10.1021/cn5000309
Furtado, D., Björnmalm, M., Ayton, S., Bush, A. I., Kempe, K., and Caruso, F. (2018). Overcoming the blood–brain barrier: the role of nanomaterials in treating neurological diseases. Adv. Mater. 30, 1801362. doi:10.1002/adma.201801362
Gao, D., Li, P., Gao, F., Feng, Y., Li, X., Li, D., et al. (2022). Preparation and multitarget anti-AD activity study of chondroitin sulfate lithium in AD mice induced by combination of D-Gal/AlCl3. Oxidative Med. Cell. Longev. 2022, 9466166. doi:10.1155/2022/9466166
Gomes, L. M. F., Bataglioli, J. C., Jussila, A. J., Smith, J. R., Walsby, C. J., and Storr, T. (2019). Modification of Aβ peptide aggregation via covalent binding of a series of Ru(III) complexes. Front. Chem. 7, 838. doi:10.3389/fchem.2019.00838
Gong, L., Sun, J., and Cong, S. (2023). Levels of iron and iron-related proteins in Alzheimer’s disease: a systematic review and meta-analysis. J. Trace Elem. Med. Biol. 80, 127304. doi:10.1016/j.jtemb.2023.127304
González-Domínguez, R., García, A., García-Barrera, T., Barbas, C., and Gómez-Ariza, J. L. (2014). Metabolomic profiling of serum in the progression of Alzheimer’s disease by capillary electrophoresis–mass spectrometry. Electrophoresis 35, 3321–3330. doi:10.1002/elps.201400196
Gorantla, N. V., Landge, V. G., Nagaraju, P. G., Priyadarshini CG, P., Balaraman, E., and Chinnathambi, S. (2019). Molecular cobalt(II) complexes for tau polymerization in Alzheimer’s disease. ACS Omega 4, 16702–16714. doi:10.1021/acsomega.9b00692
Grosas, A. B., Kalimuthu, P., Smith, A. C., Williams, P. A., Millar, T. J., Bernhardt, P. V., et al. (2014). The tachykinin peptide neurokinin B binds copper(I) and silver(I) and undergoes quasi-reversible electrochemistry: towards a new function for the peptide in the brain. Neurochem. Int. 70, 1–9. doi:10.1016/j.neuint.2014.03.002
Hampel, H., Ewers, M., Bürger, K., Annas, P., Mörtberg, A., Bogstedt, A., et al. (2009). Lithium trial in Alzheimer’s disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. J. Clin. Psychiatry 70, 922–931. doi:10.4088/jcp.08m04606
Hanzha, V. V., Rozumna, N. M., Kravenska, Y. V., Spivak, M.Ya., and Lukyanetz, E. A. (2023). The effect of cerium dioxide nanoparticles on the viability of hippocampal neurons in Alzheimer’s disease modeling. Front. Cell. Neurosci. 17, 1131168. doi:10.3389/fncel.2023.1131168
Harford, C., and Sarkar, B. (1997). Amino terminal Cu(II)- and Ni(II)-Binding (ATCUN) motif of proteins and peptides: metal binding, DNA cleavage, and other properties. Acc. Chem. Res. 30, 123–130. doi:10.1021/ar9501535
He, Z., Han, S., Zhu, H., Hu, X., Li, X., Hou, C., et al. (2020). The protective effect of vanadium on cognitive impairment and the neuropathology of Alzheimer’s disease in APPSwe/PS1dE9 mice. Front. Mol. Neurosci. 13, 21. doi:10.3389/fnmol.2020.00021
He, Z., You, G., Liu, Q., and Li, N. (2021). Alzheimer’s disease and diabetes mellitus in comparison: the therapeutic efficacy of the vanadium compound. Int. J. Mol. Sci. 22, 11931. doi:10.3390/ijms222111931
Hill, A. M., Cutler, J. B. R., and Robinson, K. (2019). “Medications to treat neurodegenerative diseases,” in Synopsis of neurology, psychiatry and related systemic disorders (Cambridge University Press), 767–773. doi:10.1017/9781107706866.038
Houldsworth, A. (2023). Role of oxidative stress in neurodegenerative disorders: a review of reactive oxygen species and prevention by antioxidants. Brain Commun. 6, fcad356. doi:10.1093/braincomms/fcad356
Huang, X., Xu, J., and Du, W. (2019). Assembly behavior of amylin fragment hIAPP19-37 regulated by Au(III) complexes. J. Inorg. Biochem. 201, 110807. doi:10.1016/j.jinorgbio.2019.110807
Huang, E., Li, H., Han, H., Guo, L., Liang, Y., Huang, Z., et al. (2024). Polydopamine-coated kaempferol-loaded MOF nanoparticles: a novel therapeutic strategy for postoperative neurocognitive disorder. Int. J. Nanomedicine 19, 4569–4588. doi:10.2147/IJN.S455492
Huffman, S. E., Yawson, G. K., Fisher, S. S., Bothwell, P. J., Platt, D. C., Jones, M. A., et al. (2020). Ruthenium(iii) complexes containing thiazole-based ligands that modulate amyloid-β aggregation. Metallomics 12, 491–503. doi:10.1039/d0mt00054j
Huntington Study Group Reach2HD Investigators (2015). Safety, tolerability, and efficacy of PBT2 in Huntington’s disease: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 14, 39–47. doi:10.1016/S1474-4422(14)70262-5
Iscen, A., Brue, C. R., Roberts, K. F., Kim, J., Schatz, G. C., and Meade, T. J. (2019). Inhibition of amyloid-β aggregation by cobalt(III) schiff base complexes: a computational and experimental approach. J. Am. Chem. Soc. 141, 16685–16695. doi:10.1021/jacs.9b06388
Jahan, R., Yousaf, M., Khan, H., Shah, S. A., Khan, A. A., Bibi, N., et al. (2023). Zinc ortho methyl carbonodithioate improved pre and post-synapse memory impairment via SIRT1/p-JNK pathway against scopolamine in adult mice. J. Neuroimmune Pharmacol. 18, 183–194. doi:10.1007/s11481-023-10067-w
Jaragh-Alhadad, L. A., and Falahati, M. (2022). Copper oxide nanoparticles promote amyloid-β-triggered neurotoxicity through formation of oligomeric species as a prelude to Alzheimer’s diseases. Int. J. Biol. Macromol. 207, 121–129. doi:10.1016/j.ijbiomac.2022.03.006
Joshi, D. C., Chavan, M. B., Gurow, K., Gupta, M., Dhaliwal, J. S., and Ming, L. C. (2025). The role of mitochondrial dysfunction in Huntington’s disease: implications for therapeutic targeting. Biomed. and Pharmacother. 183, 117827. doi:10.1016/j.biopha.2025.117827
Kalaiselvi, S., Manimaran, V., and Damodharan, N. (2020). Nanoparticle as a powerful tool to penetrate the blood-brain barrier in the treatment of neurodegenerative disease: focus on recent advances. Res. J. Pharm. Technol. 13, 2135. doi:10.5958/0974-360X.2020.00384.4
Kang, J., Nam, J. S., Lee, H. J., Nam, G., Rhee, H.-W., Kwon, T.-H., et al. (2019). Chemical strategies to modify amyloidogenic peptides using iridium(iii) complexes: coordination and photo-induced oxidation. Chem. Sci. 10, 6855–6862. doi:10.1039/C9SC00931K
Kenche, V. B., Hung, L. W., Perez, K., Volitakes, I., Ciccotosto, G., Kwok, J., et al. (2013). Development of a platinum complex as an anti-amyloid agent for the therapy of Alzheimer’s disease. Angew. Chem. Int. Ed. 52, 3374–3378. doi:10.1002/anie.201209885
Khan, A. M., Korzeniowska, B., Gorshkov, V., Tahir, M., Schrøder, H., Skytte, L., et al. (2019). Silver nanoparticle-induced expression of proteins related to oxidative stress and neurodegeneration in an in vitro human blood-brain barrier model. Nanotoxicology 13, 221–239. doi:10.1080/17435390.2018.1540728
Kladnik, J., Ristovski, S., Kljun, J., Defant, A., Mancini, I., Sepčić, K., et al. (2020). Structural isomerism and enhanced lipophilicity of pyrithione ligands of organoruthenium(II) complexes increase inhibition on AChE and BuChE. Int. J. Mol. Sci. 21, 5628. doi:10.3390/ijms21165628
La Manna, S., Leone, M., Iacobucci, I., Annuziata, A., Di Natale, C., Lagreca, E., et al. (2022). Glucosyl platinum(II) complexes inhibit aggregation of the C-terminal region of the Aβ peptide. Inorg. Chem. 61, 3540–3552. doi:10.1021/acs.inorgchem.1c03540
La Manna, S., Di Natale, C., Panzetta, V., Leone, M., Mercurio, F. A., Cipollone, I., et al. (2024a). A diruthenium metallodrug as a potent inhibitor of amyloid-β aggregation: synergism of mechanisms of action. Inorg. Chem. 63, 564–575. doi:10.1021/acs.inorgchem.3c03441
La Manna, S., Panzetta, V., Di Natale, C., Cipollone, I., Monti, M., Netti, P. A., et al. (2024b). Comparative analysis of the inhibitory mechanism of Aβ1–42 aggregation by diruthenium complexes. Inorg. Chem. 63, 10001–10010. doi:10.1021/acs.inorgchem.4c01218
Lazzara, C. A., and Kim, Y.-H. (2015). Potential application of lithium in Parkinson’s and other neurodegenerative diseases. Front. Neurosci. 9, 403. doi:10.3389/fnins.2015.00403
Lefèvre, M., Malikidogo, K. P., Esmieu, C., and Hureau, C. (2022). Sequence–activity relationship of ATCUN peptides in the context of Alzheimer’s disease. Molecules 27, 7903. doi:10.3390/molecules27227903
Leroy, K., Ando, K., Héraud, C., Yilmaz, Z., Authelet, M., Boeynaems, J.-M., et al. (2010). Lithium treatment arrests the development of neurofibrillary tangles in mutant tau transgenic mice with advanced neurofibrillary pathology. J. Alzheimers Dis. 19, 705–719. doi:10.3233/JAD-2010-1276
Levi, S., and Volonté, M. A. (2023). Iron chelation in early Parkinson’s disease. Lancet Neurol. 22, 290–291. doi:10.1016/S1474-4422(23)00039-X
Li, A., Tyson, J., Patel, S., Patel, M., Katakam, S., Mao, X., et al. (2021). Emerging nanotechnology for treatment of Alzheimer’s and Parkinson’s disease. Front. Bioeng. Biotechnol. 9, 672594. doi:10.3389/fbioe.2021.672594
Liu, W., Hu, X., Zhou, L., Tu, Y., Shi, S., and Yao, T. (2020). Orientation-inspired perspective on molecular inhibitor of tau aggregation by curcumin conjugated with ruthenium(II) complex scaffold. J. Phys. Chem. B 124, 2343–2353. doi:10.1021/acs.jpcb.9b11705
Liu, Y., Hong, H., Xue, J., Luo, J., Liu, Q., Chen, X., et al. (2021). Near-infrared radiation-assisted drug delivery nanoplatform to realize blood–brain barrier crossing and protection for parkinsonian therapy. ACS Appl. Mat. Interfaces 13, 37746–37760. doi:10.1021/acsami.1c12675
Liu, Y., Ma, J., Zhang, Q., Wang, Y., and Sun, Q. (2024). Mechanism of metal complexes in Alzheimer’s disease. Int. J. Mol. Sci. 25, 11873. doi:10.3390/ijms252211873
López-Espinosa, J., Park, P., Holcomb, M., Godin, B., and Villapol, S. (2024). Nanotechnology-driven therapies for neurodegenerative diseases: a comprehensive review. Ther. Deliv. 15, 997–1024. doi:10.1080/20415990.2024.2401307
Lovell, M. A., Robertson, J. D., Teesdale, W. J., Campbell, J. L., and Markesbery, W. R. (1998). Copper, iron and zinc in Alzheimer’s disease senile plaques. J. Neurological Sci. 158, 47–52. doi:10.1016/S0022-510X(98)00092-6
Lovestone, S., Davis, D. R., Webster, M.-T., Kaech, S., Brion, J.-P., Matus, A., et al. (1999). Lithium reduces tau phosphorylation: effects in living cells and in neurons at therapeutic concentrations. Biol. Psychiatry 45, 995–1003. doi:10.1016/S0006-3223(98)00183-8
Maass, F., Michalke, B., Willkommen, D., Canaslan, S., Schmitz, M., Bähr, M., et al. (2021). Cerebrospinal fluid iron-ferritin ratio as a potential progression marker for parkinson's Disease. Mov. Disord. 36, 2967–2969. doi:10.1002/mds.28790
Macdonald, A., Briggs, K., Poppe, M., Higgins, A., Velayudhan, L., and Lovestone, S. (2008). A feasibility and tolerability study of lithium in Alzheimer’s disease. Int. J. Geriatric Psychiatry 23, 704–711. doi:10.1002/gps.1964
Manna, S. L., Florio, D., Iacobucci, I., Napolitano, F., Benedictis, I. D., Malfitano, A. M., et al. (2021). A comparative study of the effects of platinum (II) complexes on β-amyloid aggregation: potential neurodrug applications. Int. J. Mol. Sci. 22, 3015. doi:10.3390/ijms22063015
Matarazzo, M., Pérez-Soriano, A., Vafai, N., Shahinfard, E., Cheng, K. J. C., McKenzie, J., et al. (2024). Misfolded protein deposits in Parkinson’s disease and Parkinson’s disease-related cognitive impairment, a [11C]PBB3 study. NPJ Park. Dis. 10, 96. doi:10.1038/s41531-024-00708-z
McLoughlin, C. D., Nevins, S., Stein, J. B., Khakbiz, M., and Lee, K. (2024). Overcoming the blood–brain barrier: multifunctional nanomaterial-based strategies for targeted drug delivery in neurological disorders. Small Sci. 4, 2400232. doi:10.1002/smsc.202400232
Medscape (2025). Medscape. Available online at: https://reference.medscape.com/(Accessed February 28, 2025).
Mendake, R. A., Hatwar, P. R., Bakal, R. L., Hiwe, K. A., and Barewar, S. S. (2024). Advance and opportunities in nanoparticle drug delivery for central nervous system disorders: a review of current advances. GSC Biol. Pharm. Sci. 27, 044–058. doi:10.30574/gscbps.2024.27.3.0222
Miller, L. M., Wang, Q., Telivala, T. P., Smith, R. J., Lanzirotti, A., and Miklossy, J. (2006). Synchrotron-based infrared and X-ray imaging shows focalized accumulation of Cu and Zn co-localized with β-amyloid deposits in Alzheimer’s disease. J. Struct. Biol. 155, 30–37. doi:10.1016/j.jsb.2005.09.004
Mistretta, M., Farini, A., Torrente, Y., and Villa, C. (2023). Multifaceted nanoparticles: emerging mechanisms and therapies in neurodegenerative diseases. Brain 146, 2227–2240. doi:10.1093/brain/awad014
Mital, M., Sęk, J. P., and Ziora, Z. M. (2020). Metal–peptide complexes to study neurodegenerative diseases. Methods Mol. Biol. 2103, 323–336. doi:10.1007/978-1-0716-0227-0_22
Mittal, P., and Agrawal, N. (2024). “An overview of neurodegenerative disorders,” in Altered metabolism: a major contributor of comorbidities in neurodegenerative diseases (Singapore: Springer Nature Singapore), 1–27. doi:10.1007/978-981-97-4288-2_1
Nehmeh, B., Rebehmed, J., Nehmeh, R., Taleb, R., and Akoury, E. (2024). Unlocking therapeutic frontiers: harnessing artificial intelligence in drug discovery for neurodegenerative diseases. Drug Discov. Today 29, 104216. doi:10.1016/j.drudis.2024.104216
Niu, J., Tsai, H.-H., Hoi, K. K., Huang, N., Yu, G., Kim, K., et al. (2019). Aberrant oligodendroglial–vascular interactions disrupt the blood–brain barrier, triggering CNS inflammation. Nat. Neurosci. 22, 709–718. doi:10.1038/s41593-019-0369-4
Noble, W., Planel, E., Zehr, C., Olm, V., Meyerson, J., Suleman, F., et al. (2005). Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc. Natl. Acad. Sci. U.S.A. 102, 6990–6995. doi:10.1073/pnas.0500466102
Ogonowski, N. S., García-Marín, L. M., Fernando, A. S., Flores-Ocampo, V., and Rentería, M. E. (2024). Impact of genetic predisposition to late-onset neurodegenerative diseases on early life outcomes and brain structure. Transl. Psychiatry 14, 185. doi:10.1038/s41398-024-02898-9
Ong, S. C., Tay, L. X., Ong, H. M., Tiong, I. K., Ch‘ng, A. S. H., and Parumasivam, T. (2025). Annual societal cost of Alzheimer’s disease in Malaysia: a micro-costing approach. BMC Geriatr. 25, 154. doi:10.1186/s12877-025-05717-y
Pamphlett, R., and Bishop, D. P. (2023). The toxic metal hypothesis for neurological disorders. Front. Neurol. 14, 1173779. doi:10.3389/fneur.2023.1173779
Pandini, G., Satriano, C., Pietropaolo, A., Gianì, F., Travaglia, A., La Mendola, D., et al. (2016). The inorganic side of NGF: copper(II) and zinc(II) affect the NGF mimicking signaling of the N-terminus peptides encompassing the recognition domain of TrkA receptor. Front. Neurosci. 10, 569. doi:10.3389/fnins.2016.00569
Pantiya, P., Thonusin, C., Chattipakorn, N., and Chattipakorn, S. C. (2020). Mitochondrial abnormalities in neurodegenerative models and possible interventions: focus on Alzheimer’s disease, Parkinson’s disease, Huntington’s disease. Mitochondrion 55, 14–47. doi:10.1016/j.mito.2020.08.003
Parkinson’s UK (2025). Dopamine agonists (pramipexole, ropinirole). Available online at: https://www.parkinsons.org.uk (Accessed February 28, 2025).
Peters, S., Broberg, K., Gallo, V., Levi, M., Kippler, M., Vineis, P., et al. (2021). Blood metal levels and amyotrophic lateral sclerosis risk: a prospective cohort. Ann. Neurology 89, 125–133. doi:10.1002/ana.25932
Pettit, L. D., Bal, W., Bataille, M., Cardon, C., Kozlowski, H., Leseine-Delstanche, M., et al. (1991). A thermodynamic and spectroscopic study of the complexes of the undecapeptide substance P, of its N-terminal fragment and of model pentapeptides containing two prolyl residues with copper ions. J. Chem. Soc. Dalton Trans. 1651, 1651. doi:10.1039/dt9910001651
Pietruszka, M., Jankowska, E., Kowalik-Jankowska, T., Szewczuk, Z., and Smużyńska, M. (2011). Complexation abilities of neuropeptide gamma toward copper(II) ions and products of metal-catalyzed oxidation. Inorg. Chem. 50, 7489–7499. doi:10.1021/ic2002942
Puranik, N., Yadav, D., and Song, M. (2023). Advancements in the application of nanomedicine in Alzheimer’s disease: a therapeutic perspective. Int. J. Mol. Sci. 24, 14044. doi:10.3390/ijms241814044
Pyun, J., McInnes, L. E., Donnelly, P. S., Mawal, C., Bush, A. I., Short, J. L., et al. (2022). Copper bis(thiosemicarbazone) complexes modulate p-glycoprotein expression and function in human brain microvascular endothelial cells. J. Neurochem. 162, 226–244. doi:10.1111/jnc.15609
Pyun, J., Koay, H., Runwal, P., Mawal, C., Bush, A. I., Pan, Y., et al. (2023). Cu(ATSM) increases P-glycoprotein expression and function at the blood-brain barrier in C57BL6/J mice. Pharmaceutics 15, 2084. doi:10.3390/pharmaceutics15082084
Qin, C., Xia, J., Wen, Y., Wang, J., and Zhong, C. (2025). A new immunofluorescence determination of Parkinson’s disease biomarkers using silver nanoparticles. Alexandria Eng. J. 111, 404–414. doi:10.1016/j.aej.2024.10.069
Quiroz, J. A., Machado-Vieira, R., Zarate Jr, C. A., and Manji, H. K. (2010). Novel insights into lithium’s mechanism of action: neurotrophic and neuroprotective effects. Neuropsychobiology 62, 50–60. doi:10.1159/000314310
Rafati, N., Zarepour, A., Bigham, A., Khosravi, A., Naderi-Manesh, H., Iravani, S., et al. (2024). Nanosystems for targeted drug delivery: innovations and challenges in overcoming the blood-brain barrier for neurodegenerative disease and cancer therapy. Int. J. Pharm. 666, 124800. doi:10.1016/j.ijpharm.2024.124800
Rambaran, V. H., Saumya, S. M., Roy, S., Sonu, K. P., Eswaramoorthy, M., and Peter, S. C. (2020). The design, synthesis and in vivo biological evaluations of [V(IV)O(2,6-pyridine diacetatato) (H2O)2] (PDOV): featuring its prolonged glucose lowering effect and non-toxic nature. Inorganica Chim. Acta 504, 119448. doi:10.1016/j.ica.2020.119448
Rehman, F. U., Iftikhar, F., Zhao, C., Sajid, Z., and Qazi, R. E. M. (2024). “Gold nanoparticles for treatment of cerebral diseases,” in Gold nanoparticles for drug delivery (Elsevier), 251–276. doi:10.1016/B978-0-443-19061-2.00002-X
Ribeiro, T. C., Sábio, R. M., Carvalho, G. C., Fonseca-Santos, B., and Chorilli, M. (2022). Exploiting mesoporous silica, silver and gold nanoparticles for neurodegenerative diseases treatment. Int. J. Pharm. 624, 121978. doi:10.1016/j.ijpharm.2022.121978
Riccardi, C., Napolitano, F., Montesarchio, D., Sampaolo, S., and Melone, M. A. B. (2021). Nanoparticle-guided brain drug delivery: expanding the therapeutic approach to neurodegenerative diseases. Pharmaceutics 13, 1897. doi:10.3390/pharmaceutics13111897
Roberts, K. F., Brue, C. R., Preston, A., Baxter, D., Herzog, E., Varelas, E., et al. (2020). Cobalt(III) schiff base complexes stabilize non-fibrillar amyloid-β aggregates with reduced toxicity. J. Inorg. Biochem. 213, 111265. doi:10.1016/j.jinorgbio.2020.111265
Roghani, A. K., Garcia, R. I., Roghani, A., Reddy, A., Khemka, S., Reddy, R. P., et al. (2024). Treating Alzheimer’s disease using nanoparticle-mediated drug delivery strategies/systems. Ageing Res. Rev. 97, 102291. doi:10.1016/j.arr.2024.102291
Ruan, S., Li, J., Ruan, H., Xia, Q., Hou, X., Wang, Z., et al. (2024). Microneedle-mediated nose-to-brain drug delivery for improved Alzheimer’s disease treatment. J. Control. Release 366, 712–731. doi:10.1016/j.jconrel.2024.01.013
Russino, D., McDonald, E., Hejazi, L., Hanson, G. R., and Jones, C. E. (2013). The tachykinin peptide neurokinin B binds copper forming an unusual [CuII(NKB)2] complex and inhibits copper uptake into 1321N1 astrocytoma cells. ACS Chem. Neurosci. 4, 1371–1381. doi:10.1021/cn4000988
Russo, L., Giacomelli, C., Fortino, M., Marzo, T., Ferri, G., Calvello, M., et al. (2022). Neurotrophic activity and its modulation by zinc ion of a dimeric peptide mimicking the brain-derived neurotrophic factor N-terminal region. ACS Chem. Neurosci. 13, 3453–3463. doi:10.1021/acschemneuro.2c00463
Sage Therapeutics (2024). Sage therapeutics announces topline results from the phase 2 lightwave study of dalzanemdor (SAGE-718) in the treatment of mild cognitive impairment and mild dementia in Alzheimer’s disease. Available online at: https://investor.sagerx.com/news-releases/news-release-details/sage-therapeutics-announces-topline-results-phase-2-dimension (Accessed July 21, 2025).
Sales, T. A., Prandi, I. G., de Castro, A. A., Leal, D. H. S., da Cunha, E. F. F., Kuca, K., et al. (2019). Recent developments in metal-based drugs and chelating agents for neurodegenerative diseases treatments. Int. J. Mol. Sci. 20, 1829. doi:10.3390/ijms20081829
Scarpa, E., Cascione, M., Griego, A., Pellegrino, P., Moschetti, G., and De Matteis, V. (2023). Gold and silver nanoparticles in Alzheimer’s and Parkinson’s diagnostics and treatments. Ibrain 9, 298–315. doi:10.1002/ibra.12126
Shahalaei, M., Azad, A. K., Sulaiman, W. M. A. W., Derakhshani, A., Mofakham, E. B., Mallandrich, M., et al. (2024). A review of metallic nanoparticles: present issues and prospects focused on the preparation methods, characterization techniques, and their theranostic applications. Front. Chem. 12, 1398979. doi:10.3389/fchem.2024.1398979
Sheikh, A.Md., Tabassum, S., Yano, S., Abdullah, F. B., Wang, R., Ikeue, T., et al. (2024). A cationic Zn-phthalocyanine turns Alzheimer’s amyloid β aggregates into non-toxic oligomers and inhibits neurotoxicity in culture. Int. J. Mol. Sci. 25, 8931. doi:10.3390/ijms25168931
Shilo, M., Motiei, M., Hana, P., and Popovtzer, R. (2014). Transport of nanoparticles through the blood–brain barrier for imaging and therapeutic applications. Nanoscale 6, 2146–2152. doi:10.1039/C3NR04878K
Silveira, P. L., Silveira, G. d., Muller, A., and Machado-de-Ávila, R. (2021). Advance in the use of gold nanoparticles in the treatment of neurodegenerative diseases: new perspectives. Neural Regen. Res. 16, 2425. doi:10.4103/1673-5374.313040
Singh, S., Navale, G. R., Agrawal, S., Singh, H. K., Singla, L., Sarkar, D., et al. (2023). Design and synthesis of piano-stool ruthenium(II) complexes and their studies on the inhibition of amyloid β (1–42) peptide aggregation. Int. J. Biol. Macromol. 239, 124197. doi:10.1016/j.ijbiomac.2023.124197
Sintov, A. C., Velasco-Aguirre, C., Gallardo-Toledo, E., Araya, E., and Kogan, M. J. (2016). Metal nanoparticles as targeted carriers circumventing the blood–brain barrier. Int. Rev. Neurobiol. 130, 199–227. doi:10.1016/bs.irn.2016.06.007
Stamler, D., Bradbury, M., Wong, C., and Offman, E. (2020). A phase 1 study of PBT434, a novel small molecule inhibitor of α-Synuclein aggregation, in adult and older adult volunteers (4871). Neurology 94, 4871. doi:10.1212/WNL.94.15_supplement.4871
Steinhoff, M. S., von Mentzer, B., Geppetti, P., Pothoulakis, C., and Bunnett, N. W. (2014). Tachykinins and their receptors: contributions to physiological control and the mechanisms of disease. Physiol. Rev. 94, 265–301. doi:10.1152/physrev.00031.2013
Su, Y., Ryder, J., Li, B., Wu, X., Fox, N., Solenberg, P., et al. (2004). Lithium, a common drug for bipolar disorder treatment, regulates amyloid-β precursor protein processing. Biochemistry 43, 6899–6908. doi:10.1021/bi035627j
Sweeney, P., Park, H., Baumann, M., Dunlop, J., Frydman, J., Kopito, R., et al. (2017). Protein misfolding in neurodegenerative diseases: implications and strategies. Transl. Neurodegener. 6, 6. doi:10.1186/s40035-017-0077-5
Tamano, H., and Takeda, A. (2015). Is interaction of amyloid β-peptides with metals involved in cognitive activity? Metallomics 7, 1205–1212. doi:10.1039/c5mt00076a
Tan, K. F., Chia, L. Y., Maki, M. A. A., Cheah, S. C., In, L. L. A., and Kumar, P. V. (2025). Gold nanocomposites in colorectal cancer therapy: characterization, selective cytotoxicity, and migration inhibition. Schmiedeb. Arch. Pharmacol. 398, 8975–9003. doi:10.1007/s00210-025-03839-z
Tapia-Arellano, A., Cabrera, P., Cortés-Adasme, E., Riveros, A., Hassan, N., and Kogan, M. J. (2024). Tau- and α-synuclein-targeted gold nanoparticles: applications, opportunities, and future outlooks in the diagnosis and therapy of neurodegenerative diseases. J. Nanobiotechnology 22, 248. doi:10.1186/s12951-024-02526-0
Teixeira, A. R. C., Antunes, J., Pinto, C. I. G., Campello, M. P. C., Santos, P., Gomes, C. M., et al. (2025). GRPR-targeted gold nanoparticles as selective radiotherapy enhancers in glioblastoma. Phys. Med. Biol. 70, 125018. doi:10.1088/1361-6560/ade222
Teleanu, D. M., Chircov, C., Grumezescu, A. M., Volceanov, A., and Teleanu, R. I. (2018). Blood-brain delivery methods using nanotechnology. Pharmaceutics 10, 269. doi:10.3390/pharmaceutics10040269
Terán, A., Ferraro, G., Sánchez-Peláez, A. E., Herrero, S., and Merlino, A. (2023). Effect of equatorial ligand substitution on the reactivity with proteins of paddlewheel diruthenium complexes: structural studies. Inorg. Chem. 62, 670–674. doi:10.1021/acs.inorgchem.2c04103
Toader, C., Dumitru, A. V., Eva, L., Serban, M., Covache-Busuioc, R.-A., and Ciurea, A. V. (2024). Nanoparticle strategies for treating CNS disorders: a comprehensive review of drug delivery and theranostic applications. Int. J. Mol. Sci. 25, 13302. doi:10.3390/ijms252413302
Vellingiri, B., Suriyanarayanan, A., Selvaraj, P., Abraham, K. S., Pasha, M. Y., Winster, H., et al. (2022). Role of heavy metals (copper (Cu), arsenic (As), cadmium (Cd), iron (Fe) and lithium (Li)) induced neurotoxicity. Chemosphere 301, 134625. doi:10.1016/j.chemosphere.2022.134625
Vilella, A., Daini, E., De Benedictis, C. A., and Grabrucker, A. M. (2020). “Targeting metal homeostasis as a therapeutic strategy for Alzheimer’s disease,” in Alzheimer’s disease: drug discovery (Brisbane, Australia: Exon Publications), 83–98. doi:10.36255/exonpublications.alzheimersdisease.2020.ch5
Villemagne, V. L., Rowe, C. C., Barnham, K. J., Cherny, R., Woodward, M., Bozinosvski, S., et al. (2017). A randomized, exploratory molecular imaging study targeting amyloid β with a novel 8-OH quinoline in Alzheimer’s disease: the PBT2-204 imagine study. Alzheimer's and Dementia Transl. Res. and Clin. Interventions 3, 622–635. doi:10.1016/j.trci.2017.10.001
Wall, B. J., Will, M. F., Yawson, G. K., Bothwell, P. J., Platt, D. C., Apuzzo, C. F., et al. (2021). Importance of hydrogen bonding: Structure–Activity relationships of ruthenium(III) complexes with pyridine-based ligands for Alzheimer’s disease therapy. J. Med. Chem. 64, 10124–10138. doi:10.1021/acs.jmedchem.1c00360
Wang, A., Walden, M., Ettlinger, R., Kiessling, F., Gassensmith, J. J., Lammers, T., et al. (2024). Biomedical metal–organic framework materials: perspectives and challenges. Adv. Funct. Mater. 34, 2308589. doi:10.1002/adfm.202308589
Warren Olanow, C., Kieburtz, K., Rascol, O., Poewe, W., Schapira, A. H., Emre, M., et al. (2013). Factors predictive of the development of Levodopa-induced dyskinesia and wearing-off in Parkinson’s disease. Mov. Disord. 28, 1064–1071. doi:10.1002/mds.25364
Waseem, W., Anwar, F., Saleem, U., Ahmad, B., Zafar, R., Anwar, A., et al. (2022). Prospective evaluation of an amide-based zinc scaffold as an anti-alzheimer agent: in vitro,, in vivo,, and computational studies. ACS Omega 7, 26723–26737. doi:10.1021/acsomega.2c03058
Wei, D., Freydenzon, A., Guinebretiere, O., Zaidi, K., Yang, F., Ye, W., et al. (2025). Ten years preceding a diagnosis of neurodegenerative disease in Europe and Australia: medication use, health conditions, and biomarkers associated with Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. EBioMedicine 113, 105585. doi:10.1016/j.ebiom.2025.105585
Wilson, D. M., Cookson, M. R., Van Den Bosch, L., Zetterberg, H., Holtzman, D. M., and Dewachter, I. (2023). Hallmarks of neurodegenerative diseases. Cell 186, 693–714. doi:10.1016/j.cell.2022.12.032
Wimo, A., Seeher, K., Cataldi, R., Cyhlarova, E., Dielemann, J. L., Frisell, O., et al. (2023). The worldwide costs of dementia in 2019. Alzheimer's and Dementia 19, 2865–2873. doi:10.1002/alz.12901
Wu, D., Chen, Q., Chen, X., Han, F., Chen, Z., and Wang, Y. (2023). The blood–brain barrier: structure, regulation, and drug delivery. Signal Transduct. Target. Ther. 8, 217. doi:10.1038/s41392-023-01481-w
Wu, C. Y., Chen, H.-J., Wu, Y.-C., Tsai, S.-W., Liu, Y.-H., Bhattacharya, U., et al. (2023). Highly efficient singlet oxygen generation by BODIPY–ruthenium(II) complexes for promoting neurite outgrowth and suppressing tau protein aggregation. Inorg. Chem. 62, 1102–1112. doi:10.1021/acs.inorgchem.2c03017
Xu, J., Minobe, E., and Kameyama, M. (2022). Ca2+ dyshomeostasis links risk factors to neurodegeneration in Parkinson’s disease. Front. Cell. Neurosci. 16, 867385. doi:10.3389/fncel.2022.867385
Yang, Y., Wang, Y., Jiang, X., Mi, J., Ge, D., Tong, Y., et al. (2024). Modified Ce/Zr-MOF nanoparticles loaded with curcumin for Alzheimer’s disease via multifunctional modulation. Int. J. Nanomedicine 19, 9943–9959. doi:10.2147/IJN.S479242
Yao, J., He, Z., You, G., Liu, Q., and Li, N. (2023). The deficits of insulin signal in Alzheimer’s disease and the mechanisms of vanadium compounds in curing AD. Curr. Issues Mol. Biol. 45, 6365–6382. doi:10.3390/cimb45080402
Yawson, G. K., Huffman, S. E., Fisher, S. S., Bothwell, P. J., Platt, D. C., Jones, M. A., et al. (2021). Ruthenium(III) complexes with imidazole ligands that modulate the aggregation of the amyloid-β peptide via hydrophobic interactions. J. Inorg. Biochem. 214, 111303. doi:10.1016/j.jinorgbio.2020.111303
Yawson, G. K., Will, M. F., Huffman, S. E., Strandquist, E. T., Bothwell, P. J., Oliver, E. B., et al. (2022). A dual-pronged approach: a ruthenium(III) complex that modulates amyloid-β aggregation and disrupts its formed aggregates. Inorg. Chem. 61, 2733–2744. doi:10.1021/acs.inorgchem.1c01651
Ye, H., Li, H., and Gao, Z. (2018). Copper binding induces nitration of NPY under nitrative stress: complicating the role of NPY in Alzheimer’s disease. Chem. Res. Toxicol. 31, 904–913. doi:10.1021/acs.chemrestox.8b00128
Yu, D., Guan, Y., Bai, F., Du, Z., Gao, N., Ren, J., et al. (2019). Metal–organic frameworks harness Cu chelating and photooxidation against amyloid β aggregation in vivo. Chem. – A Eur. J. 25, 3489–3495. doi:10.1002/chem.201805835
Zafar, R., Naureen, H., Zubair, M., Shahid, K., Saeed Jan, M., Akhtar, S., et al. (2021a). Prospective application of two new pyridine-based zinc (II) amide carboxylate in management of Alzheimer’s disease: synthesis, characterization, computational and in vitro approaches. Drug Des. Dev. Ther. 15, 2679–2694. doi:10.2147/DDDT.S311619
Zafar, R., Zubair, M., Ali, S., Shahid, K., Waseem, W., Naureen, H., et al. (2021b). Zinc metal carboxylates as potential anti-alzheimer’s candidate: in vitro anticholinesterase, antioxidant and molecular docking studies. J. Biomol. Struct. Dyn. 39, 1044–1054. doi:10.1080/07391102.2020.1724569
Zatta, P., Drago, D., Bolognin, S., and Sensi, S. L. (2009). Alzheimer’s disease, metal ions and metal homeostatic therapy. Trends Pharmacol. Sci. 30, 346–355. doi:10.1016/j.tips.2009.05.002
Zhang, X., Heng, X., Li, T., Li, L., Yang, D., Zhang, X., et al. (2011). Long-term treatment with lithium alleviates memory deficits and reduces amyloid-β production in an aged Alzheimer’s disease transgenic mouse model. J. Alzheimer’s Dis. 24, 739–749. doi:10.3233/JAD-2011-101875
Zhang, X., Zhang, X., Zhong, M., Zhao, P., Guo, C., Li, Y., et al. (2021). A novel Cu(II)-binding peptide identified by phage display inhibits Cu2+-mediated aβ aggregation. Int. J. Mol. Sci. 22, 6842. doi:10.3390/ijms22136842
Zhang, Q., Liu, Y., Wu, J., Zeng, L., Wei, J., Fu, S., et al. (2022). Structure and mechanism behind the inhibitory effect of water soluble metalloporphyrins on Aβ1–42 aggregation. Inorg. Chem. Front. 9, 1520–1532. doi:10.1039/D1QI01434J
Zhang, J., Zhang, Y., Wang, J., Xia, Y., Zhang, J., and Chen, L. (2024). Recent advances in Alzheimer’s disease: mechanisms, clinical trials and new drug development strategies. Signal Transduct. Target. Ther. 9, 211. doi:10.1038/s41392-024-01911-3
Zhang, W., Xiao, D., Mao, Q., and Xia, H. (2023). Role of neuroinflammation in neurodegeneration development. Signal Transduct. Target. Ther. 8, 267. doi:10.1038/s41392-023-01486-5
Zhang, Y. Y., Li, X.-S., Ren, K.-D., Peng, J., and Luo, X.-J. (2023). Restoration of metal homeostasis: a potential strategy against neurodegenerative diseases. Ageing Res. Rev. 87, 101931. doi:10.1016/j.arr.2023.101931
Zhang, Z., Sun, J., Li, Y., Yang, K., Wei, G., and Zhang, S. (2023). Ameliorative effects of pine nut peptide-zinc chelate (Korean pine) on a mouse model of Alzheimer’s disease. Exp. Gerontol. 183, 112308. doi:10.1016/j.exger.2023.112308
Zhao, L., Lan, T., Jiang, G., and Yan, B. (2022). Protective effect of the gold nanoparticles green synthesized by Calendula officinalis L. extract on cerebral ischemia stroke-reperfusion injury in rats: a preclinical trial study. Inorg. Chem. Commun. 141, 109486. doi:10.1016/j.inoche.2022.109486
Zhou, H., Jing, S., Xiong, W., Zhu, Y., Duan, X., Li, R., et al. (2023). Metal-organic framework materials promote neural differentiation of dental pulp stem cells in spinal cord injury. J. Nanobiotechnology 21, 316. doi:10.1186/s12951-023-02001-2
Keywords: neurodegenerative diseases, metal complexes, metal organic framework, metallic nanoparticles, metallopeptides, blood brain barrier, drug delivery, metal ion regulation
Citation: Tan KT, Cheong KW, Wong LC, Bertrand HC, Abd Karim NH, Chong YK and Low ML (2025) Metals in medicine: unlocking new avenues for neurodegenerative disease treatment. Front. Chem. Biol. 4:1696058. doi: 10.3389/fchbi.2025.1696058
Received: 31 August 2025; Accepted: 24 September 2025;
Published: 20 October 2025.
Edited by:
Aurelia Falcicchio, National Research Council (CNR), ItalyReviewed by:
Tobilola Akingbade, University College, North Carolina Central University, United StatesCopyright © 2025 Tan, Cheong, Wong, Bertrand, Abd Karim, Chong and Low. 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: May Lee Low, bG93bWxAdWNzaXVuaXZlcnNpdHkuZWR1Lm15