Multiple Metabolites Derived from Mushrooms and Their Beneficial Effect on Alzheimer’s Diseases

Mushrooms with edible and medicinal potential have received widespread attention because of their diverse biological functions, nutritional value, and delicious taste, which are closely related to their rich active components. To date, many bioactive substances have been identified and purified from mushrooms, including proteins, carbohydrates, phenols, and vitamins. More importantly, molecules derived from mushrooms show great potential to alleviate the pathological manifestations of Alzheimer’s disease (AD), which seriously affects the health of elderly people. Compared with current therapeutic strategies aimed at symptomatic improvement, it is particularly important to identify natural products from resource-rich mushrooms that can modify the progression of AD. This review summarizes recent investigations of multiple constituents (carbohydrates, peptides, phenols, etc.) isolated from mushrooms to combat AD. In addition, the underlying molecular mechanisms of mushroom metabolites against AD are discussed. The various mechanisms involved in the antiAD activities of mushroom metabolites include antioxidant and anti-neuroinflammatory effects, apoptosis inhibition, and stimulation of neurite outgrowth, etc. This information will facilitate the application of mushroom-derived products in the treatment of AD. However, isolation of new metabolites from multiple types of mushrooms and further in vivo exploration of the molecular mechanisms underlying their antiAD effect are still required.


Introduction
During the past two hundred years, as food quality, medical care, and lifestyles have continually improved, the elderly population has proportionally increased [1]. It is reported that 9% of the global population is older than 65, and this number is estimated to reach 17% by 2050 [2]. The health problems of elderly people cannot be ignored. Today, Alzheimer's disease (AD) is one of the neurodegenerative diseases (NDs) with a high incidence rate; these are disorders characterized by progressive dysfunction and death of neurons that seriously affect the health of many elderly people [3][4][5]. It is reported that the number of patients suffering from NDs was approximately 50 million in 2019, and it is estimated that this number will continue to increase to 152 million by 2060 [6]. If no effective prevention and treatment strategy is proposed, the number of Americans over 65 years old with AD is estimated to increase from 6.5 million to 13.8 million between 2022 and 2060 [7]. Furthermore, it is worth noting that a systematic analysis of the widespread corona virus disease of 2019 (COVID- 19) and AD has been recently carried out. An corona virus disease of 2019  and AD has been recently carried out. An increasing amount of data reveal that Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infections seriously damage the central nervous system (CNS) of patients, and this may further increase the incidence rate and severity of AD [8,9]. It is evident that AD is closely related to disability, motor dysfunction, dementia, and even death, thus representing a huge challenge, in particular for the elderly [10][11][12].
In recent years, as technology has developed and improved, many drug development and innovative treatment strategies for AD have emerged. However, although great efforts have been made to treat this disease, the currently available medical measures and medicines to halt its progression remain a source of frustration [10,13]. The majority of medications are targeted at the transient relief of the symptoms of AD rather than the underlying source of the disease [14]. Therefore, research on the prevention and treatment of AD is considered a global health issue. In this regard, natural functional ingredients isolated from mushrooms have been highlighted as potential innovative drugs [15,16].
Mushrooms are macroscopic fungi belonging to the Basidiomycota or Ascomycota phyla [17]. Historically, many wild mushrooms, such as Ganoderma lucidum and Cordyceps, have a wide range of edible and medicinal potential because of their diverse biological functions, nutritional value, and delicious taste, and these applications can be traced back to prehistoric times, particularly in Asian cultures [18][19][20][21][22]. Although some mushrooms have been found to be toxic, the beneficial activities of many mushrooms, including their antimicrobial, anticancer, and antioxidant properties, have been widely studied [23,24]. Additionally, mushroom resources are abundant in the world. Today, there may be as many as 140,000-160,000 mushroom species, and these diverse resources mean that mushrooms have great application potential in food, medicine, cosmetics, and other fields. However, to date, only a few species of mushrooms have been explored, accounting for only about 10% of all types of mushrooms, and of these, about 700 mushroom species have been found to be beneficial in the treatment of diseases [24,25]. Thus, there remains a large number of mushroom resources requiring further investigation.
Meanwhile, the number of articles recording the effects and molecular mechanisms of mushrooms in the treatment of NDs, and AD in particular, has gradually increased. The number of publications between 2010 and 2023 covering the potential of mushrooms to alleviate AD is shown in Figure 1. Including 2010, overall, about 86 research articles were found from the searches of the ScienceDirect database using the keywords "mushrooms" and "Alzheimer's disease". This review aims to summarize the beneficial roles of various mushroom metabolites for neuroprotection revealed in recent years, with an emphasis on AD.

The Main Targets for Treating Alzheimer's Disease
Analysis of pathophysiological mechanisms is crucial for selecting a novel drug for AD control. However, the etiology of this disease has unfortunately yet to be fully clarified, and this is a limiting factor in its prevention and control [26]. Nevertheless, the following cellular and molecular events associated with the occurrence and progression of AD are widely accepted ( Figure 2) [13,27].

Deposition of Aggregated Proteins
As essential biological macromolecules, the precise folding of proteins is particularly important for the execution of their function. Once the normal folding of proteins is broken, the sticky surface can be exposed and eventually aggregate into nonfunctional and toxic fibers [28]. In terms of pathological changes, neurotic plaques formed by amyloid beta peptide (Aβ) and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau proteins are widely found in AD patients, which ultimately induce the loss of neurons as well as synapses in patients [29,30]. The amyloid fibrils or toxic oligomers aggregated by misfolded proteins (prion protein, TAR DNA-binding protein, microtubule-associated protein tau, Aβ, etc.) are deposited in specific neuron cells or tissues to form insoluble extracellular plaques and intracellular inclusions [31][32][33]. Misfolded or aggregated proteins increase the risk of AD because they cause protein dysfunction and even enhance toxic functions, which further leads to a reduction in neurons [34][35][36]. Aβ can cause multiple toxic reactions, such as the disruption of the intracellular calcium balance, abnormal membrane potential, and acceleration of cell apoptosis and synaptic loss [37]. An increasing number of attempts have been made to prevent the formation of protein aggregates, in addition to their elimination and regulation [38].

Modulation of Oxidative Stress
Once the balance between the generation and detoxified ability of oxidants is broken, oxidative stress is formed, which is usually characterized by an obvious increase in free radicals such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) [39][40][41]. Generally, appropriate concentrations of ROS and RNS are particularly important for maintaining the normal function of living organisms as secondary messengers and can be scavenged by endogenous antioxidant systems, such as superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), etc. [39,[42][43][44][45]. However, oxidative stress can cause interference with the cell membrane function, irreversible damage to various functional cell components, including neuronal cell components (proteins, lipids, DNA, etc.), and even

Deposition of Aggregated Proteins
As essential biological macromolecules, the precise folding of proteins is particularly important for the execution of their function. Once the normal folding of proteins is broken, the sticky surface can be exposed and eventually aggregate into nonfunctional and toxic fibers [28]. In terms of pathological changes, neurotic plaques formed by amyloid beta peptide (Aβ) and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau proteins are widely found in AD patients, which ultimately induce the loss of neurons as well as synapses in patients [29,30]. The amyloid fibrils or toxic oligomers aggregated by misfolded proteins (prion protein, TAR DNA-binding protein, microtubule-associated protein tau, Aβ, etc.) are deposited in specific neuron cells or tissues to form insoluble extracellular plaques and intracellular inclusions [31][32][33]. Misfolded or aggregated proteins increase the risk of AD because they cause protein dysfunction and even enhance toxic functions, which further leads to a reduction in neurons [34][35][36]. Aβ can cause multiple toxic reactions, such as the disruption of the intracellular calcium balance, abnormal membrane potential, and acceleration of cell apoptosis and synaptic loss [37]. An increasing number of attempts have been made to prevent the formation of protein aggregates, in addition to their elimination and regulation [38].

Modulation of Oxidative Stress
Once the balance between the generation and detoxified ability of oxidants is broken, oxidative stress is formed, which is usually characterized by an obvious increase in free radicals such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) [39][40][41]. Generally, appropriate concentrations of ROS and RNS are particularly important for maintaining the normal function of living organisms as secondary messengers and can be scavenged by endogenous antioxidant systems, such as superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), etc. [39,[42][43][44][45]. However, oxidative stress can cause interference with the cell membrane function, irreversible damage to various functional cell components, including neuronal cell components (proteins, lipids, DNA, etc.), and even cell death. Additionally, there are reports concerning the deleterious effects of RNS  [39,46,47]. Hence, oxidative stress undoubtedly poses a certain threat to many diseases (cardiovascular disease, diabetes, cancer, etc.) [48][49][50]. Because of its high oxygen demand, low antioxidant capacity, and large quantity of oxidizable unsaturated fatty acids, brain tissue is extremely susceptible to oxidative damage [51]. There is a significant amount of evidence to indicate that elevated oxidative stress is also closely associated with events including neuronal injury, aging and apoptosis, and inflammatory response, further accelerating the pathological changes and cell demise associated with AD and many other NDs [52,53]. Some studies have shown that Aβ plaque is able to reduce mitochondrial redox activity and further trigger ROS accumulation. Others consider that ROS contributes to the accumulation of Aβ in individuals with AD [54][55][56]. These findings support antioxidants as popular screening targets for antiAD drugs.

Alleviation of Neuroinflammation
There is emerging evidence that neuroinflammation is an important early event in AD [57]. Neuroinflammation, the defensive response of CNS to a range of adverse stimuli such as infection, brain injury, and toxins, is a key protective strategy for the body [58,59]. However, high-level and persistent neuroinflammation also has negative effects on nervous tissue [60]. Two types of CNS glial cells, namely, microglia and astrocytes, are considered to characterize neuroinflammation [58]. Overactivated CNS glial cells can lead to the release of pro-inflammatory cytokines (interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, etc.), superoxide, free radicals, and cytotoxic mediators (nitric oxide, etc.), which may further induce neuronal death and synaptic dysfunction, inhibit neurogenesis, and worsen CNS damage through different pathways [38,61,62]. Furthermore, the production and deposition of Aβ are promoted by the cytokines and activated microglia [63][64][65].

Mitochondrial Dysfunction
Sufficient energy is particularly important for maintaining the survival and excitability of neurons, which mainly depend on the appropriate function of mitochondria. Mitochondria are widely involved in different physiological processes, including cell respiration, metabolism, energy generation through oxidative phosphorylation, intracellular signaling, cell survival and death, etc., [66,67]. In addition, ROS are generated and accumulated as by-products of the synthesis of ATP with the help of mitochondria and further destroy a variety of molecules [67,68]. Modern research shows that the accumulation of mitochondrial DNA deficiencies and mutant proteins in mitochondria, the decline of mitochondrial membrane potential (MMP), and calcium influx disorder are significant changes in delayed NDs. These pathological changes contribute to the regulation of neurotransmission and reduction in the survival of neurons [67,69]. Impaired mitochondrial biogenesis and trafficking, dysfunctional electron transport chains, imbalances in the concentration of calcium ions, and altered mitochondrial dynamics are all considered to be important pathways that participate in the occurrence and development of AD [70,71]. As a result, it is recognized that improving mitochondrial function is a potential treatment strategy to alleviate AD.

Cell Apoptosis, Necrosis, and Autophagy
Apoptosis, necrosis, and autophagy are all reported to play roles in neuronal cell death [72]. With regard to apoptosis, there is increasing evidence to confirm that neural cells with typical characteristics of apoptosis (DNA fragmentation, chromatin condensation, etc.) are present in AD and other NDs [73,74]. Apoptosis, an important process of programmed cell death (PCD), is thought to be the pathway of neuron loss in all NDs [75,76]. For example, overexpression of proapoptotic protein and downregulated antiapoptotic protein were detected in the brains of individuals with AD [73]. In addition, necrosis and autophagy are also reported to play critical roles in AD. Necrosis is mainly mediated by RIPK1 (receptor-interacting protein kinase 1), RIPK3 (receptor-interacting protein kinase 3), and MLKL (mixed lineage kinase domain-like protein), which form a complex called necrotic corpuscles, leading to necrosis [77]. It is reported that increased RIPK1 and MLKL levels are observed in AD patients. Additionally, it is widely accepted that autophagy as an intracellular degradation process is beneficial for eliminating misfolded proteins, and its relationship with NDs has received increasing attention [72]. It is also reported that a disorder of the autophagy process can promote the formation of Aβ plaque and NFTs, which further promote the release of proinflammatory factors, generation of ROS, and nerve cell death [78].

Diversity of Mushroom-Derived Metabolites Beneficial to AD and Their Possible Mechanisms
Many bioactive substances have been identified and purified from mushrooms, such as easily digested proteins, carbohydrates, terpenes, vitamins, etc. [84,85]. The diverse metabolites of mushrooms also demonstrate potential neuroprotective properties [86]. In this section, we will briefly discuss recent investigations and the possible mechanisms of important mushroom bioactive constituents for the alleviation of the pathological manifestations of AD.

Carbohydrates
Carbohydrates, particularly polysaccharides, are the main nutrients in mushrooms. Polysaccharides, which are polymers composed of monosaccharides, have been found extensively in the hyphae of mushrooms [21]. Because of their advantages of low toxicity, biodegradability, stability, and low price, various polysaccharides derived from mushrooms have been increasingly valued for their neuroprotective properties [14,87,88]. To date, numerous researchers have provided a significant amount of evidence for the application of crude or purified polysaccharides in the treatment of AD. Typical polysaccharides and oligosaccharides isolated from mushrooms, together with their protective actions against AD, are listed in Table 1. Research has also been conducted to identify the neuroprotective mechanism of mushroom polysaccharides. To date, the neuroprotective mechanisms of mushroom polysaccharides have been primarily identified as the prevention of neuronal apoptosis [89] and oxidative damage [90], the reduction of Aβ deposition [91], the inhibition of acetylcholinesterase (AChE) [92], and the regulation of neuroinflammation [93] (Figure 3).
Polysaccharides extracted from Dictyophora indusia, Pleurotus ostreatus, and Flammulina velutipes have been proven to exhibit neuroprotective effects, which are related to their ability to alleviate the increase in ROS and peroxide products levels and enhance the activity of antioxidant enzymes [90,94,95]. Amanita caesarea is a nutritional mushroom widely grown in China, and the potential use of its isolated polysaccharides has been investigated. Li et al. purified polysaccharides called ACPS from a water extract of A. caesarea. They found that pretreatment of the hippocampal neuron cell line (HT22) with ACPS before exposure to L glutamic acid ( L Glu) clearly improved the decline in cell viability, apoptosis rate, intracellular ROS level, and changes in MMP. Furthermore, improvements in abnormal behaviors were observed in AD model mice, together with reduced Aβ deposition and oxidative stress in the brain. They also found that this action of ACPS was attributed to its improvement of Nrf2-mediated oxidative stress [96]. Additionally, the polysaccharides from A. caesarea exhibit an anti-inflammatory effect and improve the cholinergic system function in vivo [97]. Similarly, Hericium erinaceus polysaccharide (HEP) reduced the neurotoxicity of pheochromocytoma cells (PC12) induced by L Glu treatment, which was reported to be related to inducing cell differentiation, blocking overload of intracellular calcium, inhibiting ROS production, and preventing mitochondrial membrane depolarization. Furthermore, it was demonstrated that HEP improved memory impairment and behavior abnormality in mice with AD established by treatment with D-galactose and  [98]. The study by Zhang et al. mentioned that a neutral polysaccharide (SCP-1) composed of a basic skeleton and branches was purified from an edible and medical mushroom, Sparassis crispa. It is noteworthy that the role of SCP-1 in the treatment of AD has also been observed in vivo. Using 16S rRNA sequencing technology, the growth of intestinal inflammation-related bacteria has been detected in AD mice treated with SCP-1, suggesting that this polysaccharide may alleviate the symptoms of AD by regulating intestinal microbiota and further inhibiting inflammation [99,100]. Additionally, as shown in Table 1, multiple polysaccharides isolated from various mushrooms, including Grifola frondosa [101], G. lucidum [102], Armillaria mellea [103], Cordyceps cicadae [104], Pleurotus eryngii [91], Inonotus obliquus [105], and Tremella fuciformis [106], are considered potential candidates for the management of AD. Polysaccharides extracted from Dictyophora indusia, Pleurotus ostreatus, and Flammulina velutipes have been proven to exhibit neuroprotective effects, which are related to their ability to alleviate the increase in ROS and peroxide products levels and enhance the activity of antioxidant enzymes [90,94,95]. Amanita caesarea is a nutritional mushroom widely grown in China, and the potential use of its isolated polysaccharides has been investigated. Li et al. purified polysaccharides called ACPS from a water extract of A. caesarea. They found that pretreatment of the hippocampal neuron cell line (HT22) with ACPS before exposure to L glutamic acid (L Glu) clearly improved the decline in cell viability, apoptosis rate, intracellular ROS level, and changes in MMP. Furthermore, improvements in abnormal behaviors were observed in AD model mice, together with reduced Aβ deposition and oxidative stress in the brain. They also found that this action of ACPS was attributed to its improvement of Nrf2-mediated oxidative stress [96]. Additionally, the polysaccharides from A. caesarea exhibit an anti-inflammatory effect and improve the cholinergic system function in vivo [97]. Similarly, Hericium erinaceus polysaccharide (HEP) reduced the neurotoxicity of pheochromocytoma cells (PC12) induced by L Glu treatment, which was reported to be related to inducing cell differentiation, blocking overload of intracellular calcium, inhibiting ROS production, and preventing mitochondrial membrane depolarization. Furthermore, it was demonstrated that HEP improved memory impairment and behavior abnormality in mice with AD established by treatment with Dgalactose and AlCl3 [98]. The study by Zhang et al. mentioned that a neutral polysaccha- In addition to polysaccharides, oligosaccharides also receive attention in terms of neuroprotection. Tello and coworkers attempted to assess the neuroprotective potential of the oligosaccharide fraction obtained from G. lucidum. They found that the changes in behavior and histopathology in rats treated with kainic acid were relieved [107]. Collectively, the above findings suggest that mushroom carbohydrates are promising candidates as therapeutic drugs for the treatment of AD.

Proteins and Peptides
Because of their diverse biological functions, high affinity with specific targets, high membrane permeability, and many other special properties, peptides are considered important screening targets by the pharmaceutical industry [119,120]. The protein content in mushrooms is relatively high, with an average of approximately 23.80 ± 9.82 g of protein per 100 g of mushroom dry weight (d.w.) [121]. As a consequence, many researchers have sought to use a variety of mushroom peptide resources in the treatment of NDs. Furthermore, there is mounting evidence that natural bioactive peptides have great antioxidant and inflammatory inhibition potential, suggesting them as promising candidates for a role in neuroprotection [122,123]. For instance, the neuroprotective activity of protein hydrolysates obtained from Pleurotus geesteranus in H 2 O 2 -injured PC12 cells was investigated by Wu et al. The data indicated the presence of a large quantity of hydrophobic amino acids in the test hydrolysates, and samples exerted a clear neuroprotective effect by reducing the ROS level and improving the antioxidant properties [121]. Another peptide (10,906 Da) called cordymin was isolated from Cordyces sinensis and Cordyceps militaris [124,125]. This peptide was first noticed for its antifungal activity, and its neuroprotective potential was subsequently discovered. Research carried out by Wang et al. demonstrated that cordymin was capable of protecting against nerve damage in the ischemic brain through anti-inflammation and improved antioxidant capacity [124]. Additionally, Wu et al. demonstrated the neuroprotective action of two novel selenium peptides (Se-P1 and Se-P2) derived from selenium-enriched C. militaris, which was attributed to their ability to modulate oxidant stress, inflammation, and gut microflora [126].
The biosynthesis of ergothioneine, a thiol derivative of histidine found in many mushrooms, has been extensively described [127]. The accumulated evidence confirms the therapeutic activity of ergothioneine against various diseases [128,129]. More importantly, some studies have revealed that a low ergothioneine level in the blood is one serious threat factor for AD [130]. Wu et al. found that a low plasma ergothioneine level can be used to predict the decline of cognition in elderly subjects [131]. Furthermore, with the help of a unique transporter called organic cation transporter 1, ergothioneine can easily cross the blood-brain barrier, which is conducive to its activity. Recent studies have demonstrated that ergothioneine is effective in resisting the negative influences of neurotoxic substances on neurons and cognitive function [132,133]. The neuroprotective effect of ergothioneine was shown to be associated with its capabilities of antineuroinflammatory, antioxidant, neurogenesis promoting, and neurotrophic factor induction capabilities [134][135][136]. With regard to AD, the potential application of ergothioneine has been explored in different models. In a transgenic Caenorhabditis elegans overexpressing the human AD Aβ peptide, ergothioneine reduced Aβ deposition [137]. The protective activity of ergothioneine against AD was further assessed by Whitmore et al. In 5XFAD model mice administered with ergothioneine, they found that amyloid plaques and oxidative stress were markedly decreased, and glucose metabolism was enhanced [138]. Thus, dietary supplementation is a way to enhance ergothioneine levels and, thereby, improve the clinical symptoms of AD. Fortunately, some mushrooms are rich in ergothioneine with amounts of 0.21-2.60 mg/g d.w., a prerequisite for dietary supplementation with ergothioneine [127]. In summary, mushrooms are a valuable resource pool of peptides that can be used to target the pathological manifestations of AD.

Phenolic Compounds
A common nutrient in mushrooms, phenolic compounds, have received extensive attention recently. These compounds can be classified into multiple classes: flavonoids, phenolic acids, tannins, coumarins, etc. [139]. There is a large amount of evidence to suggest that mushroom phenolic compounds have a wide range of health benefits, including antitumor, antioxidant, and antimicrobial properties, which were reviewed by Abdelshfy et al. [140]. However, there has been little discussion of the protective ability of mushroom phenols against NDs. Modern research suggests that there are various phenolic substances in mushrooms. It is documented that flavonoids with the contents of 6.646, 6.854, and 9.187 mg quercetin/g were found in Macrocybe gigantea J124, Lactifluus leptomerus J201, and Ramaria thindii J470, respectively [141]. Additionally, 4-hydroxybenzoic acid, gentisic acid, and 4-coumaric acid were the main phenolic acids identified in T. fuciformis, and their contents were 323, 174, and 30 mg per kilogram of dried mushrooms, respectively [142]. The amount of total polyphenol in P. ostreatus was determined to be 487.12 mg gallic acid equivalent/100 g d.w. [143]. The fact that various mushroom phenolic compounds control the pathogenesis of neuronal disease has attracted the attention of many researchers. Ethanol extract from Stereum hirsutum was found to be potent in inhibiting AChE (enzyme hydrolysis, the key neurotransmitter acetylcholine), which may be thanks to the phenolics within it [144]. Hispidin, a polyphenolic nutrient identified from the medicinal mushrooms Phellinus linteus [145], Phellinus igniarius [146], Phaeolus schweinitzii [147], etc., was first taken as an example. In the past few years, there have been attempts to increase the yield of mushroom hispidin. In a study by Liang et al., after strain screening and culture process optimization, the maximum hispidin production per gram of mycelium by P. linteus 04 was increased to 1.107 mg [148]. To elucidate the biosynthetic mechanism of hispidin in P. igniarius, Guo et al. used iTRAQ proteomic analysis in their study [146]. It was found that hispidin was able to alleviate the neuroinflammation in BV-2 microglial cells induced by nitric oxide via ROS-dependent mitogen-activated protein kinase (MAPK) signaling [149]. Others demonstrated that hispidin from Phellinus linteus is capable of inhibiting β-secretase (BACE1) competitively, thereby reducing the formation of β-amyloid, amyloid precursor protein cleavage products [150].
In addition to hispidin, hericenones, which are phenolic derivatives identified in the fruiting bodies of Hericium erinaceum [151], also demonstrate neuroprotective capability. In recent years, the beneficial potential of H. erinaceum on NDs has been widely investigated. It was demonstrated that the expression level of the nerve growth factor (NGF) gene, secretion of NGF protein, and neurite outgrowth in 1321N1 human astrocytoma cells treated with ethanol extracts of H. erinaceum were all enhanced. Furthermore, enhanced expression of NGF was also detected in the hippocampus of ddY mice administrated with H. erinaceum extracts, and this was related to c-Jun N-terminal kinase (JNK) signaling [152]. After taking supplements containing H. erinaceum for 12 weeks, the cognitive functions of subjects undergoing clinical testing clearly improved [153]. In addition, during an investigation of isolating the metabolites of H. erinaceum, multiple hericenones and their analogs were obtained, such as hericenones C and D [154]. Phan and coworkers purified hericenones B-E from the basidiocarps of H. erinaceum and discovered that NGF secretion was stimulated by hericenone E via the MEK/ERK and PI3K/Akt pathways [155]. Additionally, it is widely known that protection against endoplasmic reticulum stress-induced apoptosis on neural cells is a key target for AD treatment. An analog of hericenone F, 3-hydroxyhericenone F purified from H. erinaceum was found to have a protective capacity against endoplasmic reticulum stress-dependent Neuro2a cell death [156].
A large number of phenols were also identified from mushrooms, such as gallic acid, ferulic acid, chlorogenic acid, caffeic acid, and anthraquinone [157]. Some of these plant-derived phenolic compounds were documented to have antiND potential [158][159][160][161][162]. Whether the administration of these phenolic compounds from mushrooms can also effectively alleviate the clinical symptoms of AD remains to be explored in vitro and in vivo.

Terpenes
Terpenes are another type of secondary metabolites of mushrooms which consist of isoprene repeating units, and many terpenes such as cyathane diterpenoids, triterpenoids, and sesquiterpenes have been identified or isolated from various genera of mushrooms [163][164][165]. Some of these terpenes have also been found to exhibit the potential to improve the pathology of NDs. For example, after the application of tritepenoids from G. lucidum for a long time, the decline in the physiological function of the brain in aging mice was improved [166]. Furthermore, the antineuroinflammation capacity of ganoderic acid A, the lanostane-type triterpenoid from G. lucidum, was assessed in lipopolysaccharide (LPS)-treated BV2 microglial cells. They found that the proliferation and activation of cells induced by LPS were markedly suppressed by ganoderic acid A. Furthermore, decreased production of IL-1β, IL-6, and TNF-α and enhanced brain-derived neurotrophic factor (BDNF) expression were detected in cells treated with ganoderic acid A. The antineuroinflammatory action of ganoderic acid A was also demonstrated by activation of the farnesoid-X-receptor, a transcriptional factor involved in neuroprotective functions [167]. In AD mice, ganoderic acid A has also been proven to attenuate neuroinflammation by modulating the imbalance of the Th17/Tregs [168]. Qi et al. further attempted to assess the protective potential of ganoderic acid A in the management of AD. Their results demonstrated that ganoderic acid A was capable of accelerating clearance of intracellular Aβ and alleviating cognitive impairment in mice with AD, which were attributed to the autophagy induced by ganoderic acid A via activation of Axl (a potential therapeutic target for the central nervous system) [169]. According to the results provided by Shen et al., it was speculated that the autophagy promoted by ganoderic acid A might be related to its regulation of PADI4, the peptidyl arginine deiminase type IV, which induces the autophagy in AD cells via the Akt/mTOR pathway [170].
Recently, the protective capacity of erinacines-enriched H. erinaceus mycelia against Parkinson's disease (PD) [171], AD [172], spinocerebellar ataxia type 3 [173], age-related cognitive decline [174,175], etc. were described in a series of studies. In addition, the results of a study performed in 2020 showed that, compared with the control placebo group, patients with AD who received three capsules containing H. erinaceus mycelia (containing 5 mg/g erinacine A) showed significant neurocognition improvement [176]. The molecular mechanism of the positive activities of erinacine A may be attributed to their up-regulation of NGF expression and antineuroinflammatory and antiapoptosis effects. Following the detection of the expression of TNF-α and inducible nitric oxide synthase (iNOS), it was found that erinacine A treatment clearly decreased the expression of proinflammatory factors that activate glial cells and cell death induced by LPS. Furthermore, a neuroinflammation improvement effect was also observed in PD animal models treated with erinacine A [177]. Moreover, the iNOS/p38 MAPK-and TrkA/Erk1/2-mediated pathways were reported to participate in the neuroprotective effect of erinacine A [178,179].

Vitamins
Recently, increasing evidence points to a correlation between vitamin deficiency and nervous system diseases, including AD and PD [188]. By comparing healthy volunteers with AD patients aged >64 years old, it was found that the serum vitamin D level of participants with AD was clearly lower [189]. The contributions of vitamins K 2 , A, and E to the pathogenesis of AD were also reported [190][191][192]. These findings suggest that vitamins are potential candidates for relieving NDs.
Mushrooms are generally considered natural sources of various vitamins, in particular vitamin D 2 [193][194][195]. The fungi belonging to Basidiomycetes are rich in ergosterol, a type of sterol, which can be further metabolized into vitamin D 2 after ultra violet (UV) irradiation. Huang et al. found that about 16.88 and 12.68 µg/g of Vitamin D 2 and B 2 were present in the commercially dried fruiting bodies of mushrooms in China, respectively [196]. As well as in the fruiting bodies, the vitamins were detected in mycelium harvested after liquid fermentation. Pleurotus sapidus was exposed to UV-B during liquid culture, and up to 365 µg vitamin D 2 was determined in one gram of dried mycelium [197]. It is worth mentioning that mushroom powder containing 125-375 µg/g of vitamin D 2 was requested to be designated a novel food in 2020 [198]. Recognizing the rich vitamin resources in mushrooms, ninety volunteers participated in the study by Stepien et al. to investigate whether supplementing mushrooms with vitamin D 2 can improve vitamin D levels in adults. The data showed that intake of vitamin D2-enriched mushrooms markedly increased serum 25(OH)D 2 concentration [199]. Therefore, vitamins from mushrooms show broad application prospects in the control of AD. The majority of studies have tried to increase the vitamin D 2 content via ultraviolet irradiation of mushroom fruiting bodies. For example, the amount of vitamin D 2 in the gills of shiitake mushrooms was increased more than 20 times after exposure to UV-B [200]. However, there is little literature focusing on the antiAD activities of vitamins in mushrooms, providing significant scope for future research. For example, Bennett and coworkers proved the function of button mushrooms (Agaricus bisporus) enriched with vitamin D 2 on memory improvement in both wild and AD transgenic mice (APPswe/PS1dE9 transgenic mice) [201].

Nucleosides
In addition to the active components described above, nucleosides are another main ingredient of many mushrooms. Specifically, there are many studies on nucleosides in Cordyceps, and adenosine is considered the quality maker for the commercial application of Cordyceps extracts in Chinese Pharmacopoeia [202]. Various nucleosides, such as adenosine, cytidine, and uridine, have also been isolated because of their role in the regulation of various physiological processes (brain function, immunity, repair of gastrointestinal injury, etc.) [203].
In terms of neuroprotection, purine nucleosides from mushrooms may be promising candidate drugs for the future. The typical representative of these is cordycepin. Cordycepin, an analog of adenosine, is the natural constituent isolated from Cordyceps. It is reported that the amounts of cordycepin in the fruiting body and mycelial biomass of C. militaris stain CBS-132098 are 0.11%, and 0.182%, respectively [204]. Although the level of cordycepin is low, it exhibits a wide range of health-promoting potential applications, including neuroprotection. Evidence from the literature shows that cordycepin can regulate synaptic plasticity and overexcitation of the CA1 region, has antineuroinflammatory, antioxidation, and antiapoptosis effects, and can regulate mitochondrial dysfunction, thereby delaying the pathological changes caused by NDs [205,206]. For example, according to Olatunji et al., cordycepin alleviated the damage caused by 6-hydroxydopamine to PC12 cells, and this was attributed to its antioxidant properties and inhibition of cell apoptosis and mitochondrial dysfunction [207]. In another study, the therapeutic potential of cordycepin on neurological and cognitive impairments induced by intracerebral hemorrhage was proven via the regulation of oxidative stress [208]. Similarly, cordycepin decreased neural loss in mice with traumatic brain injuries. Furthermore, results from immunofluorescence staining, flow cytometry, and quantitative PCR showed that cordycepin treatment inhibited the proinflammatory microglia and macrophage in the cortex and striatum and increased the expression of anti-inflammatory microglia and macrophage. These data suggest that cordycepin alleviates long-term neuronal deficits [209]. Another similar study also documented that the potential mechanism of the neuroprotective effect of cordycepin is to relieve inflammatory response and nerve injury by inhibiting the release of NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasomes [210].
Similarly, there has been extensive research concerning adenosine, another key purine nucleoside. Data showed that the viability of glutamate-induced PC12 cells pre-treated with adenosine derived from C. cicadae clearly increased, while ROS and Ca 2+ levels in cells decreased. The authors mentioned that this protective property of adenosine was due to the regulation of the Bcl-2 family and a decrease in the levels of JNK, ERK, and phosphorylation of p38 [211]. In addition, the beneficial effect of other nucleosides and their derivatives from mushrooms (uridine [212], N 6 -substituted adenosine [213]) on neuroprotection was identified. Therefore, all studies indicate that mushroom nucleosides and their analogs may also be considered promising as therapeutic drugs for the treatment of AD.

Alkaloids
Alkaloids are nitrogen-containing compounds consisting of various subclasses. In addition to being widely present in plants, there is evidence to indicate that alkaloids are also important metabolites in mushrooms, with the most striking alkaloid being psilocybin derived from psilocybin mushrooms [214,215]. With the improvement in separation technology for natural products, various alkaloids were purified from mushrooms, some of which, such as corallocins and infractopicrin, have been found to have the potential to alleviate NDs [216]. The effect of the mushroom Hericium coralloides, famous in Chinese medicine, to promote NGF biosynthesis has been proven both in vitro and in vivo. Subsequently, the indole alkaloid corallocins A-C were isolated from this mushroom and were all capable of stimulating the expression of neurotrophin in human 1321N1 astrocytes [15,217]. Another pyrrole alkaloid (inotopyrrole B) was isolated from the mushroom Phelbopus portentosus by Sun et al., and its ability of neuroprotection was proven in human neuroblastoma SH-SY5Y cells damaged with H 2 O 2 [218]. Ryu et al. reported that isohericerinol A, a new isoindolinone derivative isolated from H. erinaceus, accelerated the synthesis of NGF and further stimulated the neurite outgrowth, suggesting that this substance may be able to alleviate AD symptoms. Western blot detection revealed that the expression of neurotrophins, including brain-derived neurotrophic factor (BDNF) and synaptophysin, were both enhanced in C6-N2a neuronal cells treated with isohericerinol A [219]. In the study performed by Lee et al., dictyoquinazol A-C isolated from D. indusiata was capable of reducing the risk of neurotoxicity and cell death of primary mouse cortical neurons induced by glutamate and N-methyl-D-aspartate at lower concentrations [220]. Additionally, there have been reports on the ability of other mushroom alkaloids, such as ganocochlearine A, infractopicrin, and 10-hydroxy-infractopicrin, to alleviate NDs [221,222]. Because of the neuroprotective potential of these compounds, the synthesis of isohericerinol, dictyoquinazol, and related derivatives has been continuously explored [223,224]. However, mushrooms remain the main sources of these compounds, and it is particularly important to explore their neuroprotective mechanisms in vivo.

Sterols
Compared with other components, there are few reports on the neuroprotective effects of mushroom sterols. In a study by Zhao et al., a novel sterol (matsutakone) and norsteroid (matsutoic acid) were successfully obtained from the edible mushroom Tricholoma matsutake, which is a delicious mushroom used in China. Furthermore, the AChE-inhibiting actions of these two compounds at a concentration of 50 µM were observed [225]. Ergosterol peroxide, a lipid-soluble steroid derivative, was isolated from a variety of mushrooms (G. lucidum, I. obliquus, P. ostreatus, etc.), and the weak ability of ergosterol peroxide from H. erinaceus has been demonstrated in PC12 cells [226][227][228][229]. However, although several in vitro experiments have confirmed the neuroprotective effects of mushroom sterols, further work is needed to assess the possibility and mechanisms of the aforementioned sterols in the treatment of AD in vivo, as well as the identification of new mushroom sterols.

Other Constituents
In addition to the above components, other constituents of mushrooms, such as essential oils, benzofuran derivatives, and cerebroside-A, were reported to have potential therapeutic activities for NDs, and these are also worthy of further exploration [230][231][232].

Conclusions and Future Research Prospects
Diverse mushrooms can be regarded as treasure troves of active compounds which have been widely used for both medical and food purposes. There are many research articles concerning the antiAD activity and molecular mechanisms of mushrooms. This review summarizes information regarding the therapeutic potential of the diverse metabolites from various mushrooms for neuroprotection, with particular emphasis on AD. Overall, many types of mushrooms have shown beneficial effects in alleviating AD, and these are attributed to their large number of constituents, such as polysaccharides, phenols, and peptides. The mechanisms involved in the antiAD activities of mushroom metabolites include antioxidant and antineuroinflammatory activity, apoptosis inhibition, and stimulation of neurite outgrowth, etc. The information collected in this review suggests that mushrooms and their metabolites have broad application prospects in the management of AD as well as NDs more widely. However, more work is required regarding the purification of active compounds, elucidation of their antiAD capacity and mechanisms in vivo, toxicity, improvement of their bioavailability and production, and development of related products. Significant work remains to be carried out to explore the vast untapped resources of mushrooms, including their cultivation and their medicinal and edible potential.

Conflicts of Interest:
The authors declare no conflict of interest.