Food-Derived Antioxidant Polysaccharides and Their Pharmacological Potential in Neurodegenerative Diseases

Oxidative stress is known to impair architecture and function of cells, which may lead to various chronic diseases, and therefore therapeutic and nutritional interventions to reduce oxidative damages represent a viable strategy in the amelioration of oxidative stress-related disorders, including neurodegenerative diseases. Over the past decade, a variety of natural polysaccharides from functional and medicinal foods have attracted great interest due to their antioxidant functions such as scavenging free radicals and reducing oxidative damages. Interestingly, these antioxidant polysaccharides are also found to attenuate neuronal damages and alleviate cognitive and motor decline in a range of neurodegenerative models. It has recently been established that the neuroprotective mechanisms of polysaccharides are related to oxidative stress-related pathways, including mitochondrial function, antioxidant defense system and pathogenic protein aggregation. Here, we first summarize the current status of antioxidant function of food-derived polysaccharides and then attempt to appraise their anti-neurodegeneration activities.


Introduction
Oxygen is essential for normal life of aerobic organisms. Due to its high redox potential, oxygen is inevitably involved in the production of reactive oxygen species (ROS) such as superoxide anion, hydroxyl radical and hydrogen peroxide. ROS are known to play an important role in a variety of cellular functions including signal transduction and regulation of enzyme activity [1,2]. Excessive ROS, on the other hand, can also interact with biological molecules and generate by-products such as peroxides and aldehydes, which can cause damages to architecture and function of cells [3,4]. Under normal circumstances, cells have a set of antioxidant defense system, including enzymatic antioxidants such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) and non-enzymatic antioxidants such as glutathione and vitamins, to combat excessive ROS [5,6]. However, when a detrimental stress compromises the antioxidant defense system, a fraction of ROS may escape the intrinsic clearance machinery and induce a state of oxidative stress, leading to cell dysfunction [7,8].

Reduction of Free Radical and Peroxidation Product Levels
Many food-derived polysaccharides are reported to have potent reducing power and free radical scavenging ability in vitro. For example, we have previously isolated a polysaccharide from Nostoc commune, a widespread microalga with a long history as food and medicine, and found that the polysaccharide is capable of scavenging both superoxide anion and hydroxyl radicals in vitro [66]. The antioxidant capability of polysaccharides is shown to be related with their functional groups such as hydroxyl, amino, carbonyl and carboxyl groups, e.g., the scavenging capacity of chitosan against superoxide radicals is correlated with its number of hydroxyl and amino groups [74]. The polysaccharide fractions from Zizyphus jujuba with higher uronic acid content exhibit stronger free radical scavenging activities than other polysaccharide fractions from the same species containing no uronic acid [75]. These functional groups in polysaccharides can donate hydrogen to electron-deficient free radicals to generate alkoxyl products, which accelerate intramolecular hydrogen abstraction and further induce spirocyclization reaction to prevent radical chain reaction [22,76]. Interestingly, free radicals are usually generated via transition metal ions in in vitro antioxidant assays. In Fenton reaction, for instance, ferrous ion is used to catalyze superoxide or hydrogen peroxide to generate hydroxyl radicals [77]. Therefore, the direct scavenging effect of polysaccharides against free radicals may also be through chelating ions. For example, the polysaccharide fraction GAPS-1 isolated from Aloe barbadensis has a higher chelating ability against ferrous ion and meanwhile exhibits stronger scavenging effect against hydroxyl radicals as compared to SAPS-1, another polysaccharide fraction isolated from the same species [51]. Moreover, monosaccharide composition and substitution groups of polysaccharides are reported to play important roles in their chelating capacity, e.g., the chelating ability of the polysaccharides from Zizyphus jujuba, a well-known traditional food, against ferrous ion is positively correlated with their galacturonic acid contents [50].
In addition to scavenge free radicals in vitro, antioxidant polysaccharides are also shown to reduce the levels of ROS and associated peroxidation products in cellular and animal models under oxidative stress. For instance, a polysaccharide from the common fungus Auricularia auricular is capable of increasing the survival rate and reducing the ROS level in hydrogen peroxide-stressed Caenorhabditis elegans [59], while the wheat bran-derived feruloyl oligosaccharides can reduce MDA content and suppress protein carbonyl formation in human erythrocytes exposed to 2,2 -Azobis(2-amidinopropane) dihydrochloride, a potent free radical generator [34]. It is well established that peroxidation products can modify cellular components, leading to cell damages. For instance, MDA interacts with proteins and DNA to generate covalent adducts with mutagenic and carcinogenic effects [3], while protein carbonyl groups can cause rapid degradation of proteins [78]. Therefore, reduction of peroxidation product contents may contribute to the protective effects of feruloyl oligosaccharides against oxidative stress.
Mitochondria are the main source of ROS and energy production in cells. However, mitochondrial dysfunction, including mitochondrial membrane potential (MMP) decline, respiratory chain malfunction and calcium dysregulation, can accelerate ROS generation and reduce ATP generation, leading to oxidative damage and energy deficiency [79,80]. In a vicious cycle, excessive ROS further impair mitochondrial components such as membrane lipids and DNA, resulting in a secondary mitochondrial dysfunction that amplifies oxidative stress [81,82]. Therefore, restoring mitochondrial function is a beneficial strategy to reduce oxidative impairment. Interestingly, recent reports have revealed that the antioxidant function of food-derived polysaccharides is associated with the alleviation of mitochondrial dysfunction. For example, we have recently shown that the polysaccharide DiPS from Dictyophora indusiata, an edible mushroom traditionally used for inflammatory and neural diseases, can reduce paraquat-mediated increase of ROS level through elevating MMP in C. elegans [58]. A polysaccharide from Ganoderma lucidum, a well-known mushroom traditionally used to delay ageing and enhance immune function, is able to attenuate isoproterenol-induced cardiotoxicity via increasing MMP and mitochondrial complex activity in rats [56]. In addition to mitochondria, several other biochemical pathways such as NADPH oxidase also contribute to ROS production [9]. Interestingly, a recent study has found that a polysaccharide from Sophora subprosrate, a medicinal food used for inflammatory disorders, can reduce superoxide anion in porcine circovirus type 2-infected murine macrophage RAW264.7 cells by inhibiting the expression of NADPH oxidase, which is a major enzyme responsible for generating superoxide anion in phagocytes [43]. Together, these findings demonstrate that antioxidant polysaccharides can inhibit cellular ROS generation through multiple pathways.

Improvement of the Antioxidant Defense System
A number of studies have revealed that food-derived polysaccharides can reduce oxidative stress and associated damages through modulation of antioxidant enzymes in experimental models. For example, we have recently found that the acidic polysaccharide EbPS-A1 from Epimedium brevicornum, a functional food used for a variety of medical conditions including neurological disorders, can increase oxidative survival and reduce ROS level and MDA content of both wild-type and polyglutamine (polyQ) C. elegans under paraquat-induced oxidative stress. The protective effect of EbPS-A1 against paraquat toxicity is shown to be related with increasing SOD and CAT activities [38]. Interestingly, the polysaccharides isolated from the tonic food Chuanminshen violaceum are also shown to up-regulate the mRNA expression levels of SOD isoforms and CAT and enhance the activities of these antioxidant enzymes in mice injected with D-galactose [39], an ageing-promoting agent that induces cognitive and motor performance deterioration similar to AD symptoms via oxidative stress and mitochondrial dysfunction [83].
In addition to their effect on antioxidant enzymes, several food-derived polysaccharides are also reported to have modulatory function on non-enzyme components of the cellular antioxidant system. For example, a polysaccharide from Anoectochilus roxburghii, a medicinal food used to treat a variety of chronic diseases such as hepatitis and diabetes, is shown to attenuate oxidative stress by increasing glutathione level as well as antioxidant enzyme activities in the hepatic tissue of mice injected with carbon tetrachloride, an organic chemical that can induce hepatotoxicity through increased oxidative stress [84]. Interestingly, A. roxburghii polysaccharide is also shown to reduce the mRNA levels of inflammation-related genes including tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) [52]. Oxidative stress is known to increase the expression of TNF-α, a key cytokine that promotes inflammation, while elevated TNF-α level can activate NADPH oxidase, ultimately leading to ROS overproduction [85,86].

Regulation of Oxidative Stress-Related Signaling
A number of signaling pathways, such as those involving nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE), mitogen-activated protein kinases (MAPKs), phosphoinositide 3 kinase/Akt (PI3K/Akt) and insulin/insulin-like growth factor-1 signaling (IIS), are known to be associated with cellular responses to multiple stresses including oxidative stress [87][88][89]. For instance, Nrf2, a basic region leucine-zipper transcription factor, plays an important role in cellular antioxidant response. When Nrf2 is activated, it translocates into nucleus and binds to ARE, leading to up-regulation of genes involved in cellular antioxidant and anti-inflammatory defense as well as mitochondrial protection [87]. Interestingly, some food-derived polysaccharides are recently reported to exert their antioxidant activity via Nrf2/ARE pathway in cellular and animal models. For instance, a polysaccharide from Lycium barbarum, a medicinal food traditionally used to retard ageing and improve neuronal function, is shown to attenuate ultraviolet B-induced cell viability decrease and ROS level increase in human keratinocytes HaCaT cells by promoting the nuclear translocation of Nrf2 and the expression of Nrf2-dependent ARE target genes [90]. This protective effect of L. barbarum polysaccharide can be neutralized by siRNA-mediated Nrf2 silencing, indicating an involvement of Nrf2/ARE pathway in the antioxidant effect of the polysaccharide [90]. Intriguingly, however, the above-mentioned polysaccharide DiPS is shown to increase oxidative survival through promoting nuclear translocation of transcription factor DAF-16/FOXO transcription factor but not SKN-1 (worm homologue of Nrf2) in wild-type C. elegans under paraquat exposure, demonstrating the antioxidant activity of the polysaccharide is associated with IIS, an evolutionarily conserved pathway that regulates organismal metabolism and lifespan, as DAF-16 is a key regulator in IIS [58].
Several signaling pathways related to cell death and survival are also involved in the antioxidant effect of food-derived polysaccharides. For example, hydrogen peroxide can induce apoptosis of rat pheochromocytoma PC12 cells via activation of p38 MAPK, while a polysaccharide from the fruiting bodies of the edible mushroom Morchella importuna increases the viability of hydrogen peroxide-exposed PC12 cells by inhibiting p38 MAPK phosphorylation [91]. In addition, hydrogen peroxide can inhibit the activation of PI3K/Akt signaling in human neuroblastoma SH-SY5Y cells, while sulfated polysaccharides prepared from fucoidan are able to increase the phosphorylation of PI3K/Akt and inhibit cell apoptosis [92]. Interestingly, the PI3K inhibitor LY294002 can partially prevent the beneficial role of the polysaccharide, demonstrating that modulation of PI3K/Akt pathway contributes to the protective effect of the sulfated polysaccharides against hydrogen peroxide cytotoxicity [92].
Recent studies provide clear evidence for the protective effects of food-derived polysaccharides against oxidative stress. Many polysaccharides exhibit potent reducing power, total antioxidant capacity and scavenging ability against free radicals in vitro. Moreover, some polysaccharides can decrease ROS and peroxidation product levels, improve antioxidant defense system and regulate stress-related signaling events to attenuate oxidative damage in cellular and animal models exposed to a variety of external stimuli, such as hydrogen peroxide, paraquat, ultraviolet radiation and virus. Together, these findings suggest a potential of these dietary polysaccharides to maintain health and prevent oxidative stress-related disorders.

Alleviation of Neurodegeneration by Food-Derived Antioxidant Polysaccharides
It is known that oxidative stress and chronic inflammation are two intertwined pathological events in NDD [85]. Excessive ROS can modulate inflammatory signaling to up-regulate the expression of pro-inflammatory factors such as cytokines, which act as potent stimuli in brain inflammation [93,94]. In turn, elevated inflammatory stress further provokes ROS generation via multiple pathways such as nuclear factor κB (NF-κB) signaling [85]. On the other hand, abnormal protein aggregation is known to be a common pathological hallmark of late-onset NDD. These protein aggregates, including amyloid-β peptide (Aβ) aggregates in AD and polyQ aggregates in HD, can induce neuronal damages through induction of oxidative stress, inflammation and mitochondrial dysfunction [95][96][97]. Oxidative stress can also promote the aggregation of pathogenic proteins as ROS modified-proteins tend to form aggregates [98]. In addition, a variety of chemical interventions, including excitatory amino acids such as glutamate, N-methyl-D-aspartate (NMDA) and kainic acid; neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA); and ageing-promoting agents such as D-galactose, are also shown to induce neurodegenerative symptoms via oxidative and inflammatory stresses [83,99,100]. As oxidative stress plays a pivotal role in neurodegeneration, antioxidant strategies, including food-derived antioxidant polysaccharides, are shown to attenuate neuronal damage and improve cognitive and motor functions in a range of neurodegenerative models (  Lycium barbarum LBP-III Aβ(25-35)-exposed rat primary cortical neurons Maintain neurite fasciculation and neuron integrity Caspase-3 and caspase-2 activities↓, p-PKR protein level↓ [110] Ganoderma lucidum GLA Aβ(25-35)-or Aβ42-exposed rat primary cortical neurons Apoptosis rate↓, synaptophysin immunoreactivity↑ DEVD-cleavage activity↓, protein levels of p-JNK, p-c-Jun, and p-p38↓ [111] Rubia cordifolia L.

Effects on Alzheimer's Disease
AD is characterized by amyloid plaques and neurofibrillary tangles in the brain, which lead to progressive memory loss and cognitive decline [143]. As global population ages, AD has become a major public health concern. Among therapeutic and nutritional interventions, growing evidence has shown that adequate intake of antioxidants may be helpful to reduce neuronal damages and alleviate AD symptoms [144,145]. For example, dietary intake of α-tocopherol or combined tocopherols shows beneficial effects to alleviate age-related cognitive decline and lower AD risk [146,147].
Antioxidant polysaccharides from various food sources are also found to inhibit Aβ-mediated neurotoxicity in experimental models ( Table 2). The polysaccharide PS-WNP from the medicinal food Polygonatum sibiricum, for instance, is shown to significantly attenuate Aβ-induced apoptosis of PC12 cells by alleviating mitochondrial dysfunction, regulating apoptosis-related protein Bax and Bcl-2 levels, inhibiting apoptotic executor caspase-3 activation and enhancing Akt phosphorylation [105]. In rats injected with Aβ40 aggregates, fucoidan is shown to attenuate learning and memory deficits by elevating SOD and GPx activities and decreasing MDA content, Bax/Bcl-2 ratio and caspase-3 activity in hippocampal tissue [104]. Using transgenic C. elegans models that overexpress Aβ proteins, the D. indusiata polysaccharide DiPS is shown to alleviate chemosensory behavior dysfunction, which is associated with reduction of ROS level and MDA content, increase of SOD activity and alleviation of mitochondrial dysfunction [58]. Antioxidant polysaccharides are also shown to modulate pathogenic protein aggregation, e.g., L. barbarum polysaccharides can reduce Aβ42 protein level in hippocampal tissue and improve the performance of learning and memory in APP/PS1 mice [109]. Intriguingly, L. barbarum polysaccharide is also shown to inhibit the apoptosis and reduce cleaved-tau protein level, the main component of neurofibrillary tangles in AD patients, in rat primary cortical cells exposed to homocysteine, a sulfur-containing amino acid associated with several NDD [128]. Moreover, several studies have uncovered that the regulatory effect of polysaccharides on protein aggregation is through the interaction with aggregation-prone proteins, and this effect is influenced by the chemical structure of polysaccharides. For example, four glycosaminoglycans from different animal tissues are shown to inhibit the neurotoxicity of serum amyloid P component and its interaction with Aβ, and the inhibitory efficacy is correlated with the uronic acid content in glycosaminoglycans [148]. In addition, the well-known glycosaminoglycan heparin is reported to bind with Aβ and promote amyloid fibrillogenesis, while low molecular weight heparin can prevent Aβ aggregation by blocking β-sheet formation and inhibiting fibril formation, suggesting that the molecular weight of polysaccharides may also affect their interaction with proteins [149,150]. Together, these studies demonstrate that the neuroprotective effects of food-derived polysaccharides in AD-like models correlate with their modulation of oxidative and related stresses.

Effects on Parkinson's Disease
PD is a chronic and progressive NDD characterized by selective loss of dopaminergic neurons in the substantia nigra pars compacta and abnormal accumulation of Lewy bodies in these neurons [151]. The major clinical symptoms of PD include motor symptoms such as tremor and bradykinesia, and neuropsychiatric symptoms such as cognitive decline and anxiety [152]. Current clinic therapy for PD only concentrates on symptomatic management as the available therapeutics do not prevent disease progression [153].
Recent studies have shown that several food-derived antioxidant polysaccharides are capable of inhibiting the neurotoxicity mediated by MPTP and 6-OHDA, which can selectively induce dopaminergic neuron death and cause PD-like motor deficits in experimental models ( Table 2). For instance, the polysaccharides from the seaweed Saccharina japonica and from the sea cucumber Stichopus japonicus can increase 6-OHDA-induced reduction of cell viability in SH-SY5Y cells and murine embryonic stem MES 23.5 cells, respectively [119,142]. The S. japonicus polysaccharides are shown to increase SOD activity, regulate the level of apoptosis-related proteins, inhibit NF-κB and p38 MAPK activation and activate PI3K/Akt pathway, indicating the involvement of antioxidant, anti-apoptotic and anti-inflammatory signaling pathways in its neuroprotective effect [119]. Using MPTP-injected mouse models, low molecular weight fucoidan DF and its two fractions DF1 and DF2 are shown to ameliorate dopaminergic neuron injury and prevent dopamine depletion in the substantia nigra through enhancing antioxidant enzyme activities and inhibiting neuronal apoptosis [154]. Interestingly, DF1 exerts better neuroprotective activity than DF and DF2 in general, and their monosaccharide compositions are different: DF1 is a hetero-polysaccharide with low content of fucose and high content of uronic acid and other monosaccharides, while DF2 mainly consists of fucose and galactose, suggesting that chemical composition may play an important role in the neuroprotective activity of fucoidan [154]. In addition, a polysaccharide from the edible microalga Chlorella pyrenoidosa is recently shown to reduce bradykinesia, inhibit the loss of striatal dopamine and its metabolites, and increase tyrosine hydroxylase in MPTP-injected mice [117]. The polysaccharide can also elevate the levels of small intestinal secretory immunoglobulin A, a protein that is crucial for the immune function of mucous membranes, in mice serum [117], and has been previously shown to enhance immune function [155]. As immune system dysfunction is known to contribute to PD development and progression [156], immune-related therapies may be a useful strategy to reduce disease risks and retard disease progression [157].

Effects on Huntington's Disease
HD is an autosomal-dominant neurodegenerative disorder that is clinically manifested by a variety of motor, cognitive and psychiatric deficits [158]. This disease is caused by an abnormal expanded CAG trinucleotide repeat in the huntingtin gene on the short arm of chromosome 4. In normal individuals, the average number of CAG repeats in the huntingtin gene is 17-20; when the number of repeats exceeds 36, the risk of developing HD is significantly increased [159]. The prevalence of HD varies geographically, with the highest rates in Europe (~10-15 per 100,000 individuals) and lower rates in Asia and Africa [160]. Similar with AD and PD, currently there is no efficient treatment for HD.
Among various pharmacological interventions, natural antioxidants such as epigallocatechin gallate and salidroside have been found to alleviate HD-like symptoms in transgenic cellular and animal models [161,162]. Interestingly, several recent studies have uncovered that food-derived antioxidant polysaccharides also have beneficial effects in HD-like animal models (Table 2). For example, the E. brevicornum polysaccharide EbPS-A1 can alleviate polyQ-mediated chemosensory dysfunction in transgenic C. elegans model HA759 [38], which expresses a polyQ tract of 150 glutamine repeats in amphid sensilla (ASH) neurons, leading to progressive ASH death and chemotactic behavior deficit [163]. EbPS-A1 also reduces ROS level, inhibits lipid peroxidation and enhances antioxidant enzyme activities in HA759 nematodes, indicating that the antioxidant activity of the polysaccharide contributes to its protective effect against polyQ neurotoxicity [38]. Other studies suggest that some antioxidant polysaccharides exert their neuroprotective effects by targeting polyQ aggregate itself, e.g., L. barbarum polysaccharide not only increases the viability of HEK293 cells that express mutant-huntingtin containing 160 glutamine repeats but also improves motor behavior and lifespan in HD-related transgenic mice [122]. The neuroprotective effect of L. barbarum polysaccharide against mutant-huntingtin toxicity in both cellular and mouse models are shown to be associated with reducing mutant-huntingtin levels and activating AKT [122]. These studies provide an important insight into the therapeutic potential of food-derived antioxidant polysaccharides in HD.

Effects on Other Neurodegenerative Symptoms
Several recent studies have shown that food-derived antioxidant polysaccharides are capable of inhibiting excitatory amino acid-mediated neurotoxicity, which is implicated in many NDD [99,164]. For instance, L. barbarum polysaccharide can increase cell viability and suppress JNK activation in glutamate-exposed rat primary cortical neurons [129], suggesting an involvement of MAPK pathway in the neuroprotective effect of the polysaccharide. Another example is G. lucidum polysaccharide, which is shown to alleviate epileptic symptoms and up-regulate the expression of calcium/calmodulin-dependent protein kinase II, a kinase that plays an important role in calcium transfer in neurons, in kainic acid-injected rats [123]. As calcium overload mediates excitatory amino acid-induced neurotoxicity [164], prevention of calcium transporting may contribute to this neuroprotective effect of G. lucidum polysaccharide. In addition, other chemicals can also induce cognitive impairment and behavior deficit through increase of oxidative and inflammatory stresses, and the polysaccharides isolated form mushrooms, medicinal herbs and algae are reported to attenuate neurodegenerative symptoms induced by these toxic chemicals. For instance, a polysaccharide from Pleurotus ostreatus can decrease escape latency in Morris water maze test and increase passive avoidance latency in step-down test in rats under D-galactose and aluminum chloride challenge [125]. P. ostreatus polysaccharide also reduces MDA level and elevates SOD, GPx and CAT activities [125], indicating that the behavior-improving capability of the polysaccharide correlates with reduction of oxidative stress.
A large body of evidence has confirmed that oxidative stress can interact with many other stresses to induce neurodegeneration, indicating its significant role in NDD development. Food-derived antioxidant polysaccharides are recently shown to alleviate neuronal injury, death and dysfunction through modulation of multiple oxidative stress-related pathways, including antioxidant defense system, mitochondrial function, peroxidation products, protein aggregation, inflammation and stress-related signaling (Figure 1), demonstrating their pharmacological potentials in NDD.
Nutrients 2017, 9,778 18 of 27 polysaccharide, which is shown to alleviate epileptic symptoms and up-regulate the expression of calcium/calmodulin-dependent protein kinase II, a kinase that plays an important role in calcium transfer in neurons, in kainic acid-injected rats [123]. As calcium overload mediates excitatory amino acid-induced neurotoxicity [164], prevention of calcium transporting may contribute to this neuroprotective effect of G. lucidum polysaccharide. In addition, other chemicals can also induce cognitive impairment and behavior deficit through increase of oxidative and inflammatory stresses, and the polysaccharides isolated form mushrooms, medicinal herbs and algae are reported to attenuate neurodegenerative symptoms induced by these toxic chemicals. For instance, a polysaccharide from Pleurotus ostreatus can decrease escape latency in Morris water maze test and increase passive avoidance latency in step-down test in rats under D-galactose and aluminum chloride challenge [125]. P. ostreatus polysaccharide also reduces MDA level and elevates SOD, GPx and CAT activities [125], indicating that the behavior-improving capability of the polysaccharide correlates with reduction of oxidative stress. A large body of evidence has confirmed that oxidative stress can interact with many other stresses to induce neurodegeneration, indicating its significant role in NDD development. Food-derived antioxidant polysaccharides are recently shown to alleviate neuronal injury, death and dysfunction through modulation of multiple oxidative stress-related pathways, including antioxidant defense system, mitochondrial function, peroxidation products, protein aggregation, inflammation and stress-related signaling (Figure 1), demonstrating their pharmacological potentials in NDD.  A number of extrinsic and intrinsic stresses such as proteotoxic stress, inflammatory stress and chemical interruption can stimulate oxidative stress through impairing the function of antioxidant system and mitochondria. Increase of oxidative stress can promote pathogenic protein aggregation and inflammation, eventually leading to neuronal injury, death and dysfunction via multiple biochemical pathways (solid line). However, food-derived antioxidant polysaccharides can exert beneficial effects to suppress neurodegeneration via attenuating oxidative, inflammatory and proteotoxic stresses and regulating stress-related signaling (dashed line).

Conclusions
Food-derived polysaccharides have been shown to scavenge free radicals in vitro and reduce oxidative damages in cellular and animal models, and their in vivo antioxidant capacities are related with regulation of peroxidation products, antioxidant defense system and stress-related signaling. As oxidative stress is closely associated with neurodegeneration, some antioxidant polysaccharides are also tested for their anti-NDD activity and found to attenuate neuronal damages and dysfunction in a number of neurodegenerative models. The neuroprotective effects of polysaccharide are associated with alleviation of multiple stresses, including oxidative, inflammatory and proteotoxic stresses ( Figure 1). Therefore, consumption of foods rich in antioxidant polysaccharides may not only reduce oxidative damage but also provide protection against oxidative stress-related disorders. It is noted that most recent studies focus on the antioxidant polysaccharides from terrestrial plants and fungi, and relatively less attention is paid to marine organisms although they represent a rich resource of bioactive polysaccharides. In addition, many food-derived antioxidant polysaccharides are shown to have potent immunomodulatory effects, and therefore it would be interesting to explore the involvement of immunomodulation in the neuroprotective effect of antioxidant polysaccharides.