How Nutrients and Active Compounds May Change Brain Degeneration Paths: Molecular Details, Challenges in Applying Research, and Personalized Nutrition

The basic neuro-regulators vitamins play an important role in maintaining redox balance, controlling epigenetic pathways, and facilitating neurotransmitter synthesis in highly metabolically active neural tissue. Since the brain requires an excessive amount of systemic oxygen and has lipid-rich membranes prone to peroxidation, preservation of antioxidant defense mechanisms is essential for neuronal survival (). Vitamin C and E, along with other antioxidant vitamins, act synergistically to counter reactive oxygen species and reduce lipid peroxidation, further maintaining membrane integrity, mitochondrial stability, and synaptic activity. It also involves redox recycling of vitamin C, and increasing vitamin E and glutathione-dependent antioxidant systems production, and enhancing intracellular oxidative stress responses (). Simultaneously, vitamin B-complex indirectly maintains redox-homeostasis by facilitating mitochondrial oxidative phosphorylation and Nicotinamide adenine dinucleotide/Flavin adenine dinucleotide (NAD/FAD)-dependent mitochondrial enzymatic processes that are necessary to neuronal bioenergetics (). Besides acting as antioxidants, vitamins are crucial in epigenetic regulation systems that dictate the neural gene expression over the lifetime. The carbon metabolism centrally involves folate and vitamin B12, which produce S-adenosylmethionine used in Deoxyribonucleic acid (DNA) and histone methylation interactions, neuronal differentiation, myelin survival and synaptic plasticity. These mechanisms of methylation are more interfered with by homocysteine, a neurotoxic metabolite that is associated with cortical degeneration and cognitive impairment (). Although vitamin A and D also increase epigenetic action by transcriptional regulations that are mediated by nuclear receptors, which regulate genes implicated in neurotropic signaling, calcium homeostasis, immune regulation and synaptic remodeling (). Vitamins are also required cofactors in neurotransmitters, as well synaptic control, particularly, pyridoxal phosphate (vitamin B6), which is necessary in making dopamine, γ-aminobutyric acid, and histamine, which directly affects neural circuits excitation inhibition homeostasis (). Vitamin C is also implicated in synthesis of catecholamine and mechanism of release of neurotransmitters. Thiamine and niacin stimulate the production of acetylcholine and NADdependent signaling synaptic plasticity and cognition pathways (). All these interrelated biochemical positions designate the vitamins as integrative regulators of neural homeostasis, the oxidative defense mediators, the chromatin regulators, the chromatin regulators and mediators of neural transmission in well-orchestrated neurobiological pathways. ^{14 15 16 17 18 19 15} + +

Minerals and trace elements are involved in highly regulated molecular pathways that support neuronal excitability, redox homeostasis, mitochondrial respiration, and synaptic transmission, but the small physiological concentrations over which they act make the central nervous system highly sensitive to both deficiency and toxicity (). Iron exemplifies this duality as it is an essential cofactor for cytochromes and iron-sulfur cluster-containing enzymes within the electron transport chain, and it supports oxidative phosphorylation and neurotransmitter synthesis. However, redox-active ferrous iron catalyzes Fenton chemistry that generates hydroxyl radicals, leading to initiation of lipid peroxidation, impairing membrane integrity, and precipitating ferroptotic neuronal death (). Such dysregulations which are commonly marked by the abnormal expression of transferrin receptors and ferritin sequestration of nutrients have been witnessed in substantia nigra neurons and they are mechanistically coupled to agglomerate the α-synuclein aggregations and mitochondrial impairments, hence linking the iron mal-regulation to proteotoxic stress (). Simultaneously, zinc is involved in both structural stabilization and dynamical signaling. In the physiological state, it helps in antioxidant defense by stabilizing superoxide dismutase (SOD) and controlling thiol buffering by metallothionein (). However, an overload of zinc in synapses in the process of excitotoxicity leads to destabilization of the mitochondrial membrane and activation of NADPH oxidate dependent ROS, and enhances apoptotic cascades, and the further conversion of modulator ion into an injury mediator (). Copper also serves as another example of balance between the metabolic need and redox liability. Participation as cofactor in the cytochrome c oxidase and dopamine 2-hydroxylase, copper maintains mitochondrial respiration and catecholaminergic neurotransmission, but copper perturbations trafficking proteins such as ATP7A and ATP7B disrupt intracellular disruption and initiate aberrant redox cycling, which increases oxidative stress effects on amyloidogenic processing (,). Besides redox-active metals selenium has a neuroprotective property since it is incorporated into selenoproteins, including glutathione peroxidases and thioredoxin reductases, that sustain thiol homeostasis and neutralize the impact of hydrogen peroxide (). Deficiency of selenium increases the neuroinflammatory signaling and inhibited synaptic plasticity, but adequate amounts of selenoproteins maintain mitochondrial stability (). Collectively, the integration of transporters, storage proteins, and redox-sensitive pathways determines whether these essential elements function as neuroprotective cofactors or transition into catalysts of oxidative injury and inflammatory amplification within neurodegenerative contexts.shows the essential nutrients homeostasis through specific molecular targets, including transcriptional regulators, mitochondrial pathways, redox signaling systems, and synaptic plasticity mechanisms. Their effects are context-dependent with both deficiency and toxicity potentially contributing to neuronal dysfunction and neurodegenerative processes. ^{35 36 37 38 39 40 41 42 43} Table 2

Natural products like flavonoids and polyphenols serve as antioxidants, neutralizing ROS and reducing oxidative stress. Polyphenols like resveratrol and curcumin have been demonstrated to reduce oxidative stress in neurons. These natural compounds increase the activity of antioxidant enzymes like catalase and superoxide dismutase (SOD), which protect neurons from oxidative damage and maintain cognitive function. Polyphenols are widely found in fruits, vegetables, wine, and tea that effectively reduce oxidative stress and neuroinflammation, two of the primary causes of dementia, because of their strong anti-inflammatory and antioxidant properties (). Resveratrol that is present in grapes and red wine alleviates oxidative stress and regulates inflammation to help preserve the wellbeing of neurons.research indicates that resveratrol (5–25 μM) can alleviate the generation of ROS in neurons in rat hippocampus exposed to nitric oxide free radical donors (). As per study demonstrated, resveratrol also maintains cognitive ability because it reduces microglial activity to reduce neuroinflammation in animals with AD (). Resveratrol effectively suppressed LPS induced proinflammatory factor (NO, TNF-α, and IL-1β) generation in neuron glia cultures, providing dopamine neurons in Parkinson, disease with a high level of neuroprotection. The production of these proinflammatory factors produced by LPS in the supernatant of neuron glia cells also significantly reduced by the administration of resveratrol (). Curcumin, which is derived from turmeric (L., Fam: Zingiberaceae), has been well studied for its neuroprotective properties. It reduces tau tangles, inhibits Aβ aggregation, and enhances cognitive performance in AD models (). Another polyphenol, epigallocatechin gallate (EGCG) from green tea ((L.) Kuntze, Fam: Theaceae), protects neurons by reducing inflammation and scavenging free radicals. Furthermore, flavonoids like kaempferol and quercetin inhibit the activation of microglia and astrocytes, which reduces the production of pro-inflammatory cytokines (). These actions reduce brain inflammation and may slow the onset of neurodegenerative diseases. In multiple sclerosis, quercetin promotes the proliferation and development of oligodendrocyte progenitor cells (OPCs) by preventing apoptosis and protecting them via the PI3K/Akt pathway. It lowers the microgliosis and astrocytes through the inhibition of inflammatory mediator's production that inhibits the astrocytes and microglial (). Curcumin is an effective anti-oxidant neuroinflammation through the inhibition Nf-κB, which is a requirement of inflammatory reaction in the brain (). Ginsenosides fromC. A. Mey also reduce inflammation in PD with the mediators of pro-inflammatory cytokines and labial microglia (). ^{44 45 46 47 48 49 50 51 52} In vitro Curcuma longa Camellia sinensis Panax ginseng

Alkaloids are nitrogenous secondary metabolites that are produced by both plants and microbes and have at least one nitrogen atom in a ring. They are well known for their ability to modify neurotransmitter systems and enhance cognitive performance (). Yang et al. () suggest that Trevis, Fam: Lycopodiaceae, contains an acetylcholine-deploying chemical, Huperzine A, which can enhance memory and cognitive functions and acetylcholine levels in AD. Berberine is an anti-inflammatory and glucose-metabolizing alkaloid obtained from thespecies and could be used in AD and PD models. Berberine prevents Aβ-induced microglial activation through the suppressor of cytokine signaling 1 (SOCS1), further demonstrating the value of berberine in the pathophysiology of AD (,). Moreover, berberine reduces endoplasmic reticulum stress, which consequently decreases cognitive impairments because endoplasmic reticulum stress is required to transmit through the hyperactivation of GSK-3β and phosphorylation of eukaryotic translation initiation factor-2α (eIF2α) using activation of PRKR-like endoplasmic reticulum kinase (PERK) and may even curb neurological issues by limiting this metabolic pathway (). ^{53 54 55 56 57} Berberis

Their antioxidant and anti-inflammatory qualities support the preservation of neural integrity. Ginkgolides, which are produced byL. (Fam:), have antioxidant properties and enhance blood flow, preventing conditions like dementia and cognitive decline ().inhibits the synthesis of inflammatory chemicals by preventing the release of proinflammatory mediators and cytokines, such as nitric oxide, prostaglandin E2 (PGE2), TNF-α, interleukin 6 (IL-6), and IL-1β. Additionally, it promotes the suppression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), cyclooxygenase-2 (COX-2), and 5-lipoxygenase (5-LOX), further prevents oxidative stress by blocking peroxiredoxin-1; moreover, it suppresses the expression of adhesion factors, such as vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1), which are essential for leukocyte adhesion to the blood vessel surface and subsequent migration to inflammation. In this sense, it actively works to prevent neuroinflammation (). Limonene, one of nature's most prevalent terpenes, is present in neroli, cumin, bergamot, caraway oil, dill oil, and citrus peel oil. This phytochemical can induce apoptosis by various biochemical effects, mostly anticancer, including negatively regulating antiapoptotic proteins and positively regulating pro-apoptotic factors. Its anti-inflammatory, anti-cancer, and antioxidant properties provide neuroprotection against a range of neurological disorders, including AD, stroke, and cerebral ischemia (–). In particular, limonene inhibits rotenone (ROT), which inhibits complex-1 of the mitochondrial electron transport chain. This can reduce locomotor impairments associated with PD and create a condition that resembles the behavioral and neuropathological signs of the illness. It also stops aberrant protein deposition, stops mitochondrial dysfunction, and initiates abnormal cell death (). Ginkgo biloba Ginkgoaceae G. Biloba ^{58 59 60 62 63}

There are several special natural materials found in marine habitats that may be used to treat NDs like AD and PD. Marine organisms, such as algae and sponges, produce phlorotannins and omega-3 fatty acids because they have evolved to harsh environmental conditions. Among the most widely investigated classes are marine peptides and protein hydrolysates, which suppress NF-κB and MAPK signaling (p38, ERK, JNK), thereby reducing transcription of pro-inflammatory mediators such as IL-1β, IL-6, TNF-α, iNOS, and COX-2 (). In parallel, their antioxidant properties counteract mitochondrial dysfunction and apoptotic cascades through ROS scavenging and metal chelation. Bioactive peptides from(Antarctic krill) and(sea cucumber) have been shown to improve cognitive impairment in experimental models through the regulation of acetylcholine metabolism, long-term potentiation, and inhibition of oxidative damage (). The carotenoid astaxanthin, which has both ketone and hydroxyl groups, is found in microalgae, shellfish, shrimp, trout, and salmon. It is well recognized for being a strong antioxidant with neuroprotective qualities that help in preventing oxidative stress and inflammation by triggering the antioxidant network, which comprises catalase and superoxide dismutase (SOD). Moreover, astaxanthin protects neurons in numerous neurodegenerative diseases, including AD and PD, by inhibiting inflammatory mechanisms, making it a potential anti-inflammatory drug in the CNS (,). Phenol-tannins isolated in brown algae are effective antioxidants, which can potentially counteract oxidative stress and neuroinflammation by inhibiting TNF-α, IL-1β, NADPH oxidase, as well as by activating Sirt-3 and PGC-1α pathways (). Bryostatin, a protein kinase C (PKC) potentiator derived from the brown bryozoan, enhances synaptogenesis and cognitive and behavioral impairments in rodent models of AD (). Fucoidan is a sulfated polysaccharide derived from the brown algaethat has demonstrated to decrease the effects of Aβ-and hydrogen peroxide-induced cytotoxicity in PC12 cells and points to its antioxidant and anti-amyloid properties (). ^{64 65 66 67 68 69 70} Euphausia superba Stichopus japonicus Bugula neritina Undaria pinnatifida 1 42

Xyloketal B, isolated from the mangrove fungus along the South China Sea coast, possesses anti-inflammatory, anti-apoptotic, and antioxidant properties by scavenging free oxygen radicals and reducing damage to neurons and endothelial cells. Zhao et al. () demonstrated the neuroprotective effects of xyloketal B in 2009 using anmodel of PC12 cells that had been subjected to glucose and oxygen deprivation. This study showed that mitochondrial ROS generation was markedly elevated after oxygen and glucose deprivation, whereas xyloketal B significantly reduced the MitoSOX signal intensity, suggesting that mitochondria may represent a primary target of its anti-apoptotic action in neuronal cells (). These marine natural products demonstrated multiple biological activities supporting their therapeutic potential and providing a foundation for future research.illustrates the Multimodal neuroprotective mechanisms of bioactive natural compounds in neurodegenerative diseases. ^{71 71} Figure 2 in vitro

Oxidative stress is a pathogenic driver in the most major NDs such as AD, PD, ALS, and HD, where endogenous redox buffering mechanisms are overwhelmed by excessive levels of reactive oxygen and nitrogen species and the impairment of neuronal integrity occurs. Numerous postmortem andexperiments repeatedly show that there is an early loss of glutathione and a decrease in antioxidant enzymes activity in susceptible brain areas, including the hippocampus in Alzheimer's disease and the substantia nigra in Parkinson's disease, suggesting that redox imbalance is a cause of neuron loss rather than the end-stage pathology (). Experimental models also indicate that dietary deficiency of redox supportive nutrients enhances oxidative damage, increases the rate of mitochondrial damage and enhances neuronal inflammatory signaling, and that nutrient restored dietary deficiencies improve redox resilience and neuronal survival (). The trace elements that are crucial cofactors to the glutathione peroxidases and superoxide dismutase respectively e.g., selenium and zinc are often abnormal in neurodegenerative disorders, and both deficiency and mislocalization are thought to contribute to the dysfunction of the redox enzymes () as shown in. The clinical and preclinical evidence demonstrates that the antioxidant defense can be partially restored and oxidative damage attenuated by correcting such imbalances, which underlines the idea that neuronal redox homeostasis requires an active support of enzymes based on sufficient nutrients as opposed to the passive antioxidant scavenging taking place. in vivo ^{72 140 73} Figure 3

In addition to direct antioxidant effects, nutrients have an extensive influence on redox signal networks that mediate gene expression, mitochondrial activity, and inflammatory responses in an overall systems-wide disease pathology (). The Nrf2 signaling pathway has become one of the most nutrient-sensitive pathways of cellular redox regulation, with control of transcription of antioxidant, detoxification, and mitochondrial maintenance genes. There is a neurodegenerative disease model, evidence that malfunctioning Nrf2 activation is associated with an increase in oxidative load, neuroinflammatory progression, and cognitive and motor outcomes, and dietary bioactive compounds to activate Nrf2 signaling lead to an increase in endogenous antioxidant systems and neuronal resistance (). Research involving toxin-induced and genetic models of Parkinson's and Alzheimer's disease show that nutrient-enhanced redox regulation enhances mitochondrial signaling, maintains synaptic behavior and neurodegenerative phenotypes. Redox signaling has also found to interact with the inflammatory pathways with the oxidative stress stimulating transcription factors like NF-κB that trigger chronic glial stimulation and cytokine release, redox restorations through nutrient have been demonstrated to reduce this loop of inflammatory amplification (). Beyond the direct antioxidant effects, the growing evidence suggests that these bioactive compounds exert their effects through hormetic modulation of cellular stress responses. These natural bioactive compounds, including flavonoids, polyphenols, and marine-derived metabolites, modulate redox homeostasis primarily through activation of the Nrf2 pathway and downstream phase II antioxidant enzymes such as SOD, catalase, and glutathione systems. These compounds suppress pro-inflammatory mediators, including IL-1β, IL-6, TNF-α, iNOS, and COX-2 which further reduces neuroinflammatory signaling. Their biological effects follow a hormetic dose-response relationship, where low-to-moderate doses induce adaptive cellular stress responses that enhance antioxidant effect and neuronal resilience, whereas excessive doses may impair redox balance and promote toxicity (,). This biphasic behavior highlights that bioactive compounds function as hormetic nutrients capable of modulating mitochondrial function, reducing neurotoxicity, and enhancing stress resilience pathways in a dose-dependent manner. Additionally, emerging evidence indicates that the gut-brain axis contributes to these effects, as dietary bioactives and their microbiota-derived metabolites regulate systemic redox balance and neuroinflammatory signaling. The growing evidence indicates that sustained, moderate exposure optimally activates Nrf2-driven cytoprotective mechanism and improves cognitive outcomes, whereas supraphysiological dosing may disrupt endogenous antioxidant systems (). These findings highlights dose optimization as a key determinant in translating bioactive compounds into effective neuroprotective strategies.illustrates that hermetic dose-responses of dietary polyphenols showing optimal-dose activation of neuroprotective pathways and suppression of neuroinflammatory and neurotoxic mechanisms. Together results suggest oxidative stress in NDs indicates the failure of nutrient-regulated redox signaling and not an inevitable oxidative injury, and nutrition is central to predisposition of the neurons. Instead of random antioxidant supplementation approach growing support in the evidence base that suggests adaptive redox signaling, metabolic flexibility, and mitochondrial resilience as a reasonable way of altering the progression of neurodegenerative disease. ^{74 75 76 77 140 78} Figure 4

A characteristic of neurodegenerative disorders is chronic neuroinflammation, which is now being recognized as a diet-sensitive, metabolically controlled process as opposed to a secondary response to neuronal injury. Cross-model preclinical studies of the AD, PD and other related disorders all indicate a significant effect of dietary composition on the microglial and astrocytic activation state, thus determining whether the process of inflammatory signaling is resolved adaptively or leads to persistent neurotoxicity (). Poor or pro-inflammatory diets worsen oxidative stress and trigger innate immune response such as NF-kB and inflammasome activation leading to prolonged release of pro-inflammatory cytokines, reactive nitrogen species and lipid mediators that destabilize synaptic integrity and neuronal survival. Conversely, nutrient-enriched diet intervention suppress glial priming, maintain synaptic structure and delay the progression of the disease in experimental models (). Dietary cues in glial cells trigger immunometabolic changes, mediating transition between oxidative and glycolytic states, which are the direct determinants of inflammatory phenotype. Exposure to nutrient imbalance selectively induces a glycolysis-dependent and pro-inflammatory phenotype in microglia that is marked by defective phagocytic clearance of protein aggregates and overproduction of cytokines whereas balanced nutrient signaling promotes anti-inflammatory and neurotrophic function as shown in. Similarly, astrocytes react to nutritional signals in changing lipid metabolism, antioxidant activity, and recycling of neurotransmitters and regulate neuronal excitability and inflammation tone (). Clinically, the correlation of diet- mediated regulation of neuroinflammation with neurodegenerative consequences is supportive but inconsistent, which is due to the complexity of the human dietary exposure, diversity of the disease and prolonged disease latency (). Dietary approaches to reduce oxidative stress, amyloid-β aggregation, and neuroinflammation have been effective in animal models of AD (). Various phytochemicals, such as polyphenols, omega-3 fatty acids and antioxidant vitamins, have been reported to regulate important signaling pathways, such as the Nrf2 pathway and NF-κB pathway, thereby reducing oxidative stress and inflammation (). The study shows that clinical result vitamin E supplementation has shown some evidence of slowing functional decline in clinical trials, but not significant cognitive improvement (). Similarly, omega-3 fatty acids have failed to improve outcomes in advanced Alzheimer's patients, possibly due to starting treatment too late. Resveratrol, while able to activate SIRT1 and AMPK pathways in animal models, has not significantly improved symptoms, possibly due to low bioavailability and high metabolism rates (). These observations highlight the importance of disease progression, pharmacokinetics and variability in patient responses. Most randomized controlled studies on inflammation using single-nutrient supplementation have found only small or inconclusive results, indicating the weakness of reductionist approaches that do not consider synergies between nutrients in the diet and nutrient status as well as the permeability of the blood-brain barrier. There is rising evidence of emerging translation support that whole-dietary and long-term dietary pattern intervention are better moderators of neuroinflammatory cascades, in part by the regulation of the brain-axis (). The diet-induced changes in the composition of gut microbiota and the production of microbial metabolites affect peripheral immune response, BBB function and central glial reaction which offer another inflammatory control. Combined, these results support the idea that diet-triggered neuroinflammation control can be achieved by coordinated metabolic, immune and microbial interactions, which means that long-term context-specific dietary-based interventions have a higher potential to alter neurodegenerative dysfunction than temporary anti-inflammatory treatment. ^{79 80} Figure 3 ^{81 82 83 84 85 86 87}

Mitochondrial dysfunction is a fundamental pathogenic pathway in neurodegenerative diseases, which combines upstream damages of oxidative stress, chronic inflammation and nutrient imbalance into a condition of bioenergetics failure that reduces neuronal viability (). The neurons have a unique reliance on efficient oxidative phosphorylation in the mitochondria to support synaptic transmission, axonal transport and ionic homeostasis and thus make them highly susceptible to mitochondrial signal disruption. The preclinical models of AD, PD, Huntington's disease (HD), ALS and electron transport chain all show early disruption of electron transport chain activity, diminished ATP production, appropriate mitochondrial dynamics, as well as excessive generation of reactive species before neurons are lost (). AMPK-regulated nutrient-dependent signaling pathways play leading roles in controlling mitochondrial biogenesis, antioxidant defense and mitophagy, hence ensuring good mitochondrial quality control (). It is experimentally shown that perturbation of these pathways enhances neurodegenerative phenotypes, and dietary regulation of mitochondrial signaling maintains synaptic plasticity and retards cell dysfunction. Metabolic cofactor, fatty acid, and micronutrient deficiency reduce the efficiency of the mitochondria, encourage leakage of electrons, and increase redox stress establishment of a feed-forward loop where energetic deficiency further worsens adaptive stress responses () as shown in. These findings place mitochondria not only as passive targets of neurodegeneration, but also as active integrators of nutrient-driven signaling that determines neuronal survival. On a translational scale, growing evidence indicates that nutritional regulation of mitochondrial signaling can provide a plausible approach to the improvement of neuronal survival, however, clinical validation is yet to be confirmed (). The diet-based interventions that increase metabolic flexibility in preclinical systems have been shown to improve mitochondrial respiration, stabilize the membrane potential and promote the selective elimination of dysfunctional mitochondria by a process known as mitophagy, limiting the buildup of dysfunctional organelles (). These consequences can be characterized as the enhanced functioning of the synapsis, a decrease in the neuroinflammation and a longer delay in the disease development, which highlights the interrelation of mitochondrial dysfunction with isolated metabolic supplements that have yielded diverse results with many failings to provide solid disease-modifying effects despite excellent mechanistic support. These differences can probably be seen as the complexity of human neurodegenerative disease, in which dysfunction of mitochondria is caused by the combination of aging, genetic predisposition, chronic inflammation, and lifelong dietary habits and not the deficiency of a specific biochemical pathway (). Accurate clinical and observational evidence is quickly mounting that indicates the significance of maintaining dietary habits that encourage metabolic robustness, as opposed to temporary treatments that focus on enhancing mitochondrial production. Besides, mitochondrial signaling is overlapped with the metabolic health of the whole body, such as insulin sensitivity and lipid metabolism, which connects the peripheral metabolic failure with vulnerability of brain neurons (). From this approach, mitochondrial protection in neurodegeneration is best understood as a network-level result of nutrient-driven signaling that maintains energy flexibility in the face of chronic stress. All these perspectives support the idea that the renewal of metabolic flexibility and mitochondria quality regulation via specific nutritional treatments can be one of the key strategies to maintain neuronal survival and delay neurodegenerative disease progression, especially when they are combined with other interventions aimed at redox balance and neuroinflammatory load. ^{88 89 90 91} Figure 3 ^{92 93 94 95}

Synaptic plasticity is the cellular mechanism of learning memory, and cognitive adaptability and its impairment is among the first events in neurodegenerative disease with the greatest functional relevance (). Synapses are highly metabolically active structures in the brain that demand constant energy, maintain redox, remodel dynamic membranes, and protein turnover is tightly regulated in order to maintain activity-directed plasticity (). Signaling pathways that are driven by nutrients play a role in sustaining such processes because nutrients control neurotransmitter production, synaptic vesicle cycling, receptor expressing, and cytoskeletal dynamics via metabolic and signaling intermediates. Preclinical studies in AD and PD models consistently show that delivery insufficiency exacerbates dendritic spine loss, impairs long-term potentiation, and accelerates synaptic failure, whereas nutrient-rich or metabolically supportive dietary interventions preserve synaptic architecture and improve cognitive abilities (). Nutrients have the mechanistic effect of modulating important plasticity-related signaling pathways, such as brain-derived neurotropic factor (BDNF), Cyclic AMP response element–binding protein (CREB), calcium-dependent kinases, and lipid-derived second messengers, which combine metabolic signals and neuronal activity to promote synaptic strengthening and remodeling. Interruption of these nutrient-sensitive pathways impairs the ability of synaptic flexibility, reduces the oxidative stress, inflammatory mediator and mitochondrial dysfunction threshold to damage neuronal communication, strengthening a feed-forward loop of synaptic susceptibility and cognitive impairment as shown in. Adult neurogenesis, especially in the hippocampal dentate gyrus, helps in cognitive flexibility, memory formation, and network adaptability and it is very sensitive to metabolic and nutritional status (). Neurogenic capacity is impaired in NDs and aging due to disruption of neuronal integration by impaired neural progenitor proliferation, altered differentiation programs, and inflammatory microenvironment (). Critically, neurogenesis is functionally related to synaptic plasticity, since newly formed neurons are more plastic and take an over-proportional part in circuit remodeling during learning, therefore enhancing the cognitive effects of nutrient-driven signaling (). Evidence of nutrition-mediated improvement of synaptic plasticity and neurogenesis as contributing to cognitive maintenance is still suggestive in clinical settings, as it is hard to assess synaptic and neurogenic outcomes in humans or on time scales as long as structural remodeling needs to be (). Observational studies implicate nutrient-rich dietary habits with maintained cognitive functioning and lower risk of dementia, but randomized experimental studies of specific nutrient supplementation have produced inconsistent results, probably because of variability in disease progression, initial nutritional status, and multifacetedness of synaptic signaling pathways. The PD nutritional approaches have targeted mitochondrial dysfunction, oxidative damage and inflammation. Neuroprotective effects of coenzyme Q10, creatine, and omega-3 fatty acids have been observed in experimental models, through improvements in mitochondrial bioenergetics and suppression of inflammatory agents (). However, these mechanisms have yet to translate to clinical benefit and randomized studies with coenzyme Q10 and creatine have not shown disease-modifying activity (). Similarly, omega-3 fatty acids have shown variable results in clinical trials reflect the fact that these studies were conducted at a time when significant loss of dopaminergic neurons has already occurred, and that nutritional status has not been considered in the design of the studies (). These findings suggest the importance of early intervention and individual patient characteristics for successful nutritional interventions. Taken collectively, there is an indication of breakdown in nutrient-sensitive plasticity and neurogenic signaling and not necessarily irreversible loss of synapses. Through the maintenance of synaptic plasticity, endorsing circuit renewal, and consolidating cognitive reserve, nutrient-mediated plasticity and neurogenesis processes become essential element of long term cognitive reserve in an aggregate system also comprising of redox balance, inflammatory regulation, and mitochondrial health.shows the Molecular targets and cellular specificity of nutrients and bioactives. ^{96 97 98} Figure 3 ^{99 100 101 102 103 104 105} Table 3

One of the major limitations underlying the failure of dietary polyphenols to translate from preclinical efficacy to clinical efficacy is their poor bioavailability, rapid metabolism, and limited ability to cross the BBB. The novel nanoformulation strategies have been developed to enhance the pharmacokinetic and pharmacodynamic profiles of polyphenols. These include nanoliposomes and phytosomes, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs), which improve solubility, stability, and targeted delivery of bioactive compounds. Nanoencapsulation protects polyphenols from premature degradation and facilitates their absorption which resulting to increase systemic bioavailability and enabling higher concentrations of unmetabolized active compounds to reach the brain. The preclinicalstudies demonstrated that these delivery systems increase brain uptake, improve mitochondrial function, and reduce neuroinflammatory and oxidative stress markers more effectively than free compounds. Moreover, growing evidence suggests that nano-formulated polyphenols may act synergistically with pharmacological agents, further enhancing therapeutic efficacy in clinical settings (,). These innovative approaches represent an important step toward overcoming translational barriers and converting dietary polyphenols into clinically viable neuroprotective interventions. in vivo ^{110 111}