Aldehyde-Mediated Neurotoxicity and Lutein Intervention: A Novel Therapeutic Strategy for Alzheimer’s Disease

Abstract

Alzheimer disease (AD) is a major health issue of global concern whereby there are minimal treatment options. The existing therapies, which have been recently added to the arsenal of disease-modifying anti-amyloid antibodies, provide limited clinical benefits but are characterized by a high cost and risk. This is one of the reasons why alternative approaches to address earlier, multifactorial causes of neurodegeneration are urgently required. Chronic oxidative stress is a central and early pathological alteration in AD that initiates lipid peroxidation and the production of extremely reactive and toxic ? ?-unsaturated aldehydes, including 4-hydroxynonenal (4-HNE) and acrolein. These aldehydes are direct mediators of neuronal injury and can result in covalent conjugates with proteins, mitochondrial dysfunction, and neuroinflammation and protein aggregation. The new, comprehensive hypothesis that has been suggested in this review is that the dietary carotenoid lutein is a high-affinity "molecular sponge" of these toxic aldehydes. In addition to its known antioxidant and anti-inflammatory effects, the conjugated polyene chain of lutein is postulated to react via a Michael addition reaction with electrophilic aldehydes, neutralizing them in the lipid-bi-layer, and avoiding their attack on other important cellular structures. We elaborate on the chemical logic of this interaction and synthesize preclinical evidence on in vitro and in vivo models of the ability of lutein to scavenge the aldehydes, reduce the pathological biomarkers, maintain the synaptic integrity and salvage the cognitive functioning. In addition, we comment on the pharmacokinetic difficulties of the brain delivery and present the future research directions, such as the formation of synthetic analogues, as well as the study of the role of lutein in the gut-brain axis. The potential to reduce the neuroprotective impact of AD in aldehyde toxicity cascade by targeting lutein is a good approach that is not only pleiotropic but also safer.

Keywords

Introduction

Alzheimer disease (AD) is a severe health issue in the planet that has few treatment options. The existing therapies, such as new disease-modifying anti-amyloid antibodies, have only moderate clinical improvement and are linked to a high cost and risk [1]. This highlights the necessity of alternative approaches that should focus on earlier, multifactorial predictors of neurodegeneration. Chronic oxidative stress appears to be a central and early pathological event in AD that leads to lipid peroxidation and the formation of highly reactive, toxic a,b-unsaturated aldehydes, including 4-hydroxynonenal (4-HNE) and acrolein. These aldehydes are direct intermediates of neuronal injury because they form covalent adducts with proteins, shatter mitochondrial activity, and encourage neuroinflammation and protein aggregation. One of the new and unifying hypotheses of this review is this: the dietary carotenoid lutein is a high-affinity molecular sponge to these toxic aldehydes [2]. In addition to its known antioxidant and anti-inflammatory effects, the conjugated polyene chain of lutein has been postulated to react by Michael addition with electrophilic aldehydes, which neutralizes it in the lipid bilayer and inhibits its ability to attack important cellular constituents. We elaborate on the chemical basis of this process and summarize preclinical data on the ability of lutein to neutralize aldehydes and inhibit pathological biomarkers, maintain synaptic structure and save cognitive abilities [3]. Additionally, we address the pharmacokinetic issues of the brain delivery, and comment on the future research opportunities, such as the synthetic analogues, and the discussion of lutein as a component in the gut-brain axis. Aldehyde toxicity cascade inhibitors Lutein is a promising and pleiotropic neuroprotective approach, potentially safer in AD [4-6].

Beyond Amyloid and Tau: The Role of Oxidative Stress and Lipid Peroxidation

Alzheimer disease (AD) is one of the most significant and growing medical, social, and economic issues of the 21 st century. Being marked by the malignant loss of memory, thinking, and finally identity, AD is a crisis in slow motion of millions of patients and relatives all over the world [7]. The existing pharmacotherapeutic options, namely the acetylcholinesterase inhibitors and the NMDA receptor antagonist memantine, are only symptomatic over a small period, and they have no impact on stopping or reversing the pathological progression of the disease. The recent introduction of anti-amyloid monoclonal antibodies (e.g., lecanemab, donanemab) is a historic change to disease modifying and it has been shown that, though of clinical marginal benefit, amyloid-beta plaque clearance can be statistically significant and cause a slowing of cognitive decline [8]. This progress, however, comes at a high price: the treatment effect is relatively small (a -25-35% slowing over 18 months), the cost is enormous, and the side effects, like amyloid-related imaging abnormalities (ARIA) such as cerebral edema or hemorrhage are significant and must be carefully monitored [9]. Moreover, these treatments are acting on one pathway the amyloid cascade in a disease that is now known everywhere to be extraordinarily complex and multifactorial. This creates an enormous therapeutic gap of procedures that are safer and more widely available, and can help to combat other underlying causes of neurodegeneration [10]. The need is desperate and urgent to develop new therapeutic approaches working via complementary or alternative pathways especially against the earlier and upstream events taking place in the pathological cascade that leads to neuronal susceptibility and demise. It is no longer about treating the symptoms or eliminating one pathological protein, but rather guarding the essential cell machinery of the brain against the multifactorial assaults that characterize AD [11-13].

The Aldehyde Toxicity Cascade: 4-HNE, Acrolein, and Malondialdehyde (MDA) as Key Mediators of Neuronal Damage

The past emphasis on the hallmark pathological features of AD: extracellular amyloid-beta plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau has been necessary but incomplete. The more holistic approach to AD pathogenesis shows a multi-faceted interplay of genetic, metabolic, and environmental factors that come together to form a state of chronic oxidative stress which may be the primary and initial event that stimulates amyloid and tau pathology, as well as exacerbates it [14]. The brain is particularly susceptible to oxidative damage; its rate of oxygen utilization is high, it contains relatively large amounts of lipids, with rather limited antioxidant defenses, and harbors redox-active metals, such as iron and copper. This balance is destroyed in AD [15]. The result of sustained overproduction of reactive oxygen species (ROS) is mitochondrial damage, glial cell inflammatory activation, and the redox activity of amyloid-beta itself. The process of lipid peroxidation is not passive; it is a chain reaction that destroys the cellular and organellar membrane structure. More to the point, it is a molecular factory, producing an array of highly reactive carbonyl-containing breakdown products. Although the amyloid and tau form the "tombstones" of the disease: the end-stage aggregates, lipid peroxidation and its toxic products are the bullets: the actual chemical agents of neuronal dysfunction and damage [16]. This oxidative damage in the brain is prodromal and is found in the brains of people who have mild cognitive impairment (MCI) way before fulminant dementia sets in. Therefore, focusing on the oxidative stress and lipid peroxidation cascade provides a window of opportunity to act upstream and possibly prevent the destruction of neurons, regulate the toxicity of amyloid and tau, and maintain the synaptic activity, regardless of the causative agent [17].

Lutein: From Dietary Carotenoid to Neuroprotective Agent

The dietary carotenoid lutein is also a distinctive and promising candidate in the quest to find agents that can be utilized to moderate this aldehyde attack. Long-chain and fat-soluble xanthophylls, lutein and its structural isomer zeaxanthin, are primarily involved in eye health, as they make up the macular pigment, which absorbs blue light and suppresses photo-oxidative stress. Nevertheless, there is now strong epidemiological and clinical support which implicates lutein as a key nutrient to the health of the brain [18].

Chemistry and Bioavailability

The chemical structure of lutein (C₄₀H₅₆O₂) is important in its functioning. It has a long conjugated polyene chain that has been an excellent electron-rich system in the quenching of singlet oxygen and free radicals. Importantly, hydroxyl groups are decorative at both terminuses of the molecule. These polar caps bind the molecule to lipid bi-layers, like cell membranes, and the hydrophobic chain forms the inner part [19]. This exact orientation enables lutein to stabilize membrane structure and trap oxidative agents on the very site of lipid peroxidation initiation, which is the cell membrane. Lutein is bioavailable; although it is not synthesized in humans, recommended sources are leafy greens, egg yolks and marigold flowers. It crosses blood brain barrier, and specifically it builds up in the parts of the brain that are important in thinking such as hippocampus, frontal cortex and occipital cortex [20]. It is observed that increased dietary and serum lutein levels are always related to improved cognitive functions, increased gray matter volume and lower chances of dementia in old age [21].

Mechanisms: Antioxidant, Anti-Inflammatory, and Structural Roles in The Brain

The proven neuroprotective activities of lutein are multi-complex. To start with, possessing strong antioxidant properties, its conjugated chain directly extinguishes ROS such as singlet oxygen and peroxyl radicals, and inhibits the initiation of lipid peroxidation [22]. Second, it has anti-inflammatory effects by inhibiting nuclear factor-kappa B (NF-kB) activation and following, pro-inflammatory cytokine (e.g., IL-1b, TNF-α) production in stimulated microglia to ameliorate the neuroinflammatory fire that drives neurodegeneration. Third, it is structural in the neuronal membranes [23]. Lutein is capable of increasing the level of membrane order, integrity, and cell-to-cell communication through synapses by rigidifying membrane lipid rafts, which are cholesterol-rich, cholesterol-binding microdomains that contain signaling proteins. It also promotes the activity of the gap junctions which are of extreme importance in metabolic coupling and ionic homeostasis of the neurons and the glial cells that support them. These concerted efforts enable the lutein to sustain a normal neuronal microenvironment, enhance the ability to endure metabolic stress and contribute to synaptic plasticity underlying learning and memory [24-26].

Hypothesis: Lutein as a "Molecular Sponge" for Neurotoxic Aldehydes

On the basis of its established functions, we put forward a new, consolidating, and therapeutically directed hypothesis: Lutein is a high-affinity molecular sponge or sacrificial trap of the neurotoxic a,b-unsaturated aldehydes (4-HNE, acrolein) that occurs in designing neurodegeneration in Alzheimer disease. This hypothesis goes beyond the mechanism of lutein as upstream prevention (antioxidant) downstream interception (detoxification). The chemical explanation is sound [27]. The 4-HNE and acrolein are toxic aldehydes that are very strong electrophiles because the carbonyl and its adjacent double bond (the a, b-unsaturated system) is electron-withdrawing. The conjugated polyene chain of Lutein is electron rich and nucleophilic. This preconditions a typical Michael addition reaction, in which the nucleophilic carbon atoms of the lutein chain are covalently bonded to the electrophilic b-carbon of the aldehyde and the reaction is stabilized. This response is quite effective in countering the active carbonyl of the aldehyde, before it can attack and crippling important proteins, DNA, or other cellular nucleophiles such as glutathione [28-30]. In this regard, lutein would serve as a chemical defense line. It would saturate or sponge diffusible aldehydes in the lipid bilayer--where they are produced and whence they give their attacks. Such would have a number of important effects: (1) Direct Cytoprotection: Protection of the activity of important enzymes, transporters, and mitochondrial proteins. (2) Glutathione Protection: The finite and essential glutathione reserves of the cell are not lost to aldehyde assault. (3) Prevention of Protein Aggregation: Prevention of cross-linking and hyperphosphorylation of proteins such as tau by aldehyde. (4) signaling inhibition: Prevention of aldehyde-mediated activation of pro-apoptotic and pro-inflammatory stress signaling [31]. Consequently, we hypothesise that much of the neuroprotective and cognitive effects of lutein which are reported can be due not only to its antioxidant effects, but also this explicit, chemical de-toxification of the major cytotoxic agents Fig.1. Clinical application of this hypothesis will entail maximizing the delivery of lutein to the brain, proving that adduct formation of lutein in vivo in AD models, and that this particular process results in functional preservation and cognitive salvaging [32]. A lutein-based intervention might address the gap that currently exists in the AD therapeutic toolbox: safe, pleiotropic, disease-modifying, an intervention approach that targets neurons at the most fundamental level: at the membrane where the destruction occurs [33].

Fig: 1 Schematic overview of the aldehyde-mediated pathogenesis in Alzheimer's disease and the hypothesized therapeutic intervention by lutein

From Chemistry to Neuroprotection: Biological Consequences in Neural Systems

The mechanical basis of the interaction between aldehyde and lutein relies on a particular chemical reaction, which is the Michael addition, and is motivated by the difference in the electronic properties of the reactants. Αβ-unsaturated aldehydes such as acrolein and 4-HNE are potent electrophiles because the carbonyl group removes the electrons, and it is strengthened by the occurrence of another double bond [34]. The long conjugated polyene chain of lutein has an electron-rich nucleophilic system. This enables a nucleophilic carbon in the chain of lutein to become electrophilically activated and assail the electrophilic b-carbon of the aldehyde to create a carbon-carbon bond and to create a stable, covalent lutein-aldehyde complex. This irreversibly deprotonates the reactive carbonyl of the aldehyde, avoiding the attack on essential cellular reactive centers. The first step in the validation of this mechanism is through the in silico studies, including the molecular docking which is a model of the interaction, and it aims to predict the location of reactive site and thermodynamic preference [35]. This is then followed by in vitro spectroscopic validation by methods such as LC-MS/MS and NMR that allow one to conclusively determine the distinct mass and structural signature of the lutein-4-HNE or lutein-acrolein adducts. Cell-free systems subsequently show functionality detoxification where lutein defends model proteins against carbonyl generation, maintains the activity of enzymes and spares glutathione loss by competitively binding to aldehydes. In biological examples of the neurons, this chemical contact is transformed into essential neuroprotective effects [36]. It has a direct protective effect on cases of aldehyde-induced mitochondrial dysfunction preservation of membrane potential, ATP production, and mitigation of reactive oxygen species generation. It greatly diminishes cross-linking of proteins through aldehydes and aggregation, especially the existence of 4-HNE-tau adducts and tau hyperphosphorylation. Moreover, lutein suppresses the production of pro-inflammatory cytokines by acting on key inflammatory cascades, including NF-kB activation and NLRP3 inflammasome formation in glial cells by sequestration of aldehydes that are signaling molecules [37]. Lastly, it is synergistic with the cellular antioxidant system; lutein upholds cellular glutathione by being a sacrificial nucleophile, and can enhance the Nrf2 pathway by inhibiting aldehyde-mediated inactivation of its regulator, Keap1, thus enhancing the overall antioxidant response of the cell. This series of studies--of basic covalent chemistry to total cellular defense--constitutes the mechanistic core of arguing in favor of lutein as a therapeutic agent of aldehyde-scavenging in Alzheimer disease [38].

Preclinical Proof-of-Concept

In vitro Studies in Neuronal and Glial Cell Cultures

The direct protective relationship between lutein and aldehyde-induced toxicity is only established in vitro in neuronal and glial cell cultures, and is the essential translational step in the transformation of biochemical mechanism to cellular efficacy [39]. These in vitro studies usually use two paradigms: direct testing of exogenous, pathophysiological concentrations of aldehydes such as 4-HNE or acrolein, and indirect tests in which the production of aldehydes in cells by stressors, such as amyloid-beta oligomers or mitochondrial inhibitors, is tested. The basic technique is to pre-treat human cell lines of neurons or primary neurons with a lutein concentration gradient (e.g. 0.1-10 µM) to permit membrane integration, then the toxic insult. Protection is measured by using a tiered method of analysis starting with viability tests (MTT, CCK-8) to produce typical sigmoidal dose-response patterns, which indicates the half-maximal effective concentration (EC₅₀) and therapeutic window [40]. This is succeeded by mechanistic validation, that is, lutein pre-treatment dose-dependently decreases intracellular pool of free, reactive aldehydes and reduces global formation of carbonyl adducts on proteins as quantified by fluorescent of immunoblotting Fig.2. More importantly, it also maintains the activity of particular aldehyde-sensitive objects, including the activity of mitochondrial complexes and glutamate transporters [41]. Parealle cell culture experiments in microglia are concerned with functional modulation, in which lutein inhibits the pro-inflammatory cytokine release and pathways of activation induced by aldehyde (TNF-a, IL-1b) and inhibits activation pathways. Taken together, such studies form the basis of a solid in vitro pharmacokinetic-pharmacodynamic (PK-PD) profile, the minimal effective concentration, the optimal dose of lutein to protect cells and glials, which offers the necessary proof-of-concept that the chemical scavenging ability of lutein can be translated into real to rescue neuronal and glial health in a concentration-dependent manner [42-45].

Fig: 2 Mitochondrial dynamics and apoptosis regulation

Fig: 3 Effects of lutein on antioxidant parameters and cytokine levels in a rodent model

Fig: 4 Experimental timelines for lutein administration and behavioral assessments

Pharmacokinetics and Brain Biodistribution Studies

The therapeutic target of any neuroprotective agent is essentially determined by its capacity to arrive at their site of action at effective concentrations. Thus, thorough pharmacodynamic (PD) and pharmacokinetic (PK) investigations are essential, which would cross the line of proof-of-concept, establishing the realistic parameters of using lutein [65]. The initial severe obstacle is Blood-Brain Barrier (BBB) Penetration. The rate of passive diffusion across lipid bilayers is favored by the lipophlily character of lutein, which contains a long-conjugated hydrocarbon chain, which proposes a priori the possibility that lutein can penetrate the BBB. Nonetheless, this passive process can be constrained by the fact that it is simultaneously low water solubility and high molecular weight [66]. It has been shown that lutein is able to penetrate across the BBB, where a portion of it is deposited in certain areas of the brain such as the hippocampus and the cortex, but the bioavailability of lutein is comparatively low (between 1-5 percent of taken orally). This movement is probably aided by carotenoid transporters and lipoprotein-mediated trafficking which include its binding to high-density lipoproteins (HDLs) in the blood which could bind to scavenger receptor class B type 1 (SR-B1) on brain endothelial cells. To develop the therapeutics, this requires progressive formulation approaches e.g. lipid-based nanocarriers or phospholipid complexes to improve solubilization, degradation resistance and active promotion of receptor-mediated transcytosis across the BBB, which is essential in improving the brain lutein payload of oral intake [67]. After going over the barrier, it is important to know Brain Pharmacokinetics and Metabolism in order to determine the dosing schedule. Although the cleavage by b-carotene oxygenases is one of the most important in the periphery, its occurrence in the brain is less evident. Lutein can also be oxidized or enzymatically modified directly. More importantly, the synthesis and the equilibrium of the proposed lutein-aldehyde adduct become a primary component in its PK profile [68]. The complex analytical techniques, including tandem mass spectrometry (LC-MS/MS) of microdialysates or homogenates of the brain, will be necessary to provide the answer to these questions, as they allow monitoring not only lutein but also its metabolites and adducts over time, and construct a specific PK model of the brain. Finally, without PD, PK is meaningless as a way of showing that the drug is acting upon its target [69]. Most directly and powerfully, a dose-dependent lowering of the concentrations of the same toxins that lutein is hypothesized to counteract namely, a decrease in free 4-HNE and acrolein in brain tissue and cerebrospinal fluid (CSF). More conclusive is the quantification of particular protein-adduct loads. Researchers can demonstrate that treatment with lutein reduces the concentration of 4-HNE- or acrolein-modified proteins (i.e. 4-HNE-histidine adducts) in vulnerable brain regions significantly using immunoassays or LC-MS/MS with selective antibodies or isotopic standards. The ultimate goal of target engagement would be to directly detect the lutein-4-HNE adduct itself in the brain, which would give indisputable chemical evidence of the process in vivo [70].

Secondary, down stream bio-markers of effective aldehyde scavenging would involve a drop in wider markers of oxidative injury (protein carbonyls, 8-OHdG to DNA oxidation), a decrease in neuro inflammatory cytokines (IL- 1b, TNF-α) in CSF, and a maintenance of synaptic marker proteins (PSD- 95, synaptophysin) [71-73]. By developing a concise relationship between the brain lutein (or adduct) levels, the decrease of these pathological biomarkers, and the cognitive outcome improvement in the animal models, the formation of strong PK/PD relationship, de-risking clinical translation by defining biologically-effective dose, will be made [74,75].

Future Research Directions

To the underlying aldehyde-scavenging hypothesis, there are numerous research possibilities in the future that can generate enormous potential to increase the therapeutic efficacy and individualization of the intervention. One of the major advances has been the creation of more effective and brain-permeable synthetic analogs of lutein. The lutein scaffold is susceptible to drug design and medicinal chemistry: the polyene chain can be shortened or modified to increase chemical reactivity with aldehydes, functional groups can be added to increase aqueous solubility and BBB uptake via particular transporters, or prodrugs can be designed in whose production depends on the location of the target scavenger moiety in the brain. These second generation compounds may have better pharmacokinetics and increased molar efficiency in neutralising the aldehyde burden, which may have therapeutic effects with reduced doses. At the same time, studies should be extended to examine the effects of microbiome-derived aldehydes in the gut and the the systemic effects of lutein. Gut microbiome generates reactive carbonyl species, acrolein and malondialdehyde that may exit the intestines and possibly lead to peripheral and central oxidative stress. Research into the effect of lutein supplementation on the gut microbial community, on the production of enteric aldehydes, or on the fortification of the intestinal barrier properties would identify a new, indirect mechanism of action. This has the potential to make lutein a gut-brain axis modulator, treating a systemic toxicity cause. Lastly, incorporating digital health to aid monitoring of diet, supplement compliance, and cognitive trajectory will prove to be instrumental in the real-life translation and rigor of clinical trials. Smartphone applications might be able to monitor dietary lutein, and look at compliance with supplements through image capture or self-reports, whereas embedded cognitive games (such as digital variants of the trail-making test) may be able to measure cognitive performance frequently and sensitively. Physiological surrogates of oxidative stress or inflammation may be measured using wearable devices. This multimodal, continuous stream of data allow accurate correlation of lutein exposure (dose) with cognitive outcome, the development of personalized dosing, the earlier identification of responders, and the development of dynamic, n-of-1 therapeutic paradigms that puts the field on the path of truly precision nutrition and medicine in the prevention of Alzheimer.

CONCLUSION

The toxicity cascade in aldehydes is an excellent and convergent therapeutic site of the multifactorial pathogenesis of Alzheimer disease. Its mechanism is not limited to upstream antioxidant activity (as concluded by the hypothesis that lutein is a sacrificial "molecular sponge" to directly neutralize neurotoxic aldehydes such 4-HNE and acrolein) in its role as a downstream chemical detoxifier. The suggested measure would safeguard important cellular machineries, free up native store antioxidant resources, and alleviate major downstream diseases such as protein clumping and neuroinflammation. Preclinical studies will prove to be a good proof-of-concept showing that lutein can ease the aldehyde load, salvage neuronal performance, and enhance cognition in AD animal models. To translate this promise into clinical reality, it is necessary to overcome bioavailability issues with the help of sophisticated formulations, to prove target engagement in human beings with particular biomarkers, and to run the successful clinical trials. Provided the evidence is not invalid, the lutein supplementation might provide an accessible, safe and non-toxic, complementary approach-membrane-level security to a gap in the current AD therapeutic landscape that is highly needed, and bring the field towards a more holistic neuroprotective approach.

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