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Alzheimer's disease (AD) is a common neurodegenerative disorder. Polysaccharides have been scientifically demonstrated to possess neuroprotective properties. In this study, a polysaccharide was isolated from the fruiting bodies of Hericium coralloides using hot water extraction and purified using column chromatography. This H. coralloides polysaccharide (HCP) is a galactan with a main chain of →6)-α-d-Galp-(1 → and a molecular weight of 16.06 kDa. The partial α-l-Fucp-(1 → substitution takes place at its O-2 position. The neuroprotective effects of HCP were investigated in an APP/PS1 mouse model of Alzheimer's disease. The step-down and Morris water maze tests demonstrated that HCP effectively ameliorated cognitive impairment. After 8-week treatment, HCP reduced amyloid-β plaques and phosphorylated tau protein deposition. In combination with the gut microbiota and metabolites, proteomic analysis suggested that the neuroprotective effects of HCP are associated with neuroinflammation and autophagy. Immunofluorescence and western blotting analyses confirmed that HCP facilitated the polarization of M2 microglia by augmenting autophagy flux, thereby effectively reducing levels of amyloid-β plaques and neuroinflammation. These data demonstrate that HCP effectively mitigates neuroinflammation by enhancing autophagic flux, demonstrating its potential for the treatment of AD., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The water-soluble neutral polysaccharide BEP2, with a molecular weight of 26.65 kDa, was isolated from the aqueous extract obtained from the fruiting bodies of Boletus aereus Bull. BEP2 primarily comprises Gal, with specific site substitutions speculated at partial positions, such as the substitution of -OCH 3 at position H-3 or the branch at position C-2 including α-L-Fucp-(1→, α-D-Manp-(1 → and α-D-Manp-(1 → 3)-α-L-Fucp-(1 → 6)-β-D-Glcp-(1→. Treatment with BEP2 significantly enhanced learning, memory, and cognitive function, while concurrently reducing the accumulation of β-amyloid and suppressing neuroinflammation within the brains of APP/PS1 mice. Based on the results of biochemical detection, gut microbiota analysis, and metabolomic profiling, we found that BEP2 significantly upregulated the abundance of two bacterial families while downregulation that of seven bacterial families within the intestinal ecosystem. Notably, the abundance of the S24-7 family was significantly increased. Treatment with BEP2 upregulated five metabolites, while downregulating three metabolites, including norepinephrine. Additionally, BEP2 decreased the levels of interleukin (IL)-1β and IL-6, regulated the activities of microglial cells and astrocytes and increased the levels of the chemokine fractalkine (CX3CL1) and its receptor on microglia (CX3CR1), as well as that of transforming growth factor (TGF)-β1. These findings confirmed the suppressive effects of BEP2 on neuroinflammation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The large molecular weight of polysaccharides limits their absorption and utilization by organisms, affecting their biological activities. In this study, we purified α-1,6-galactan from Cantharellus cibarius Fr. (chanterelle) and reduced its molecular weight from approximately 20 kDa to 5 kDa (named CCP) to increase its solubility and absorption. In APP/PS1 mice, CCP improved both spatial and non-spatial memory loss in Alzheimer's disease (AD) mice, as confirmed by the Morris water maze, step-down, step-through, and novel object recognition tests, and dampened the deposition of amyloid-β plaques, as assessed by immunohistochemical analysis. Proteomic analysis suggested that the neuroprotective effects of CCP are related to anti-neuroinflammation. Immunofluorescence analysis and western blotting confirmed that CCP attenuated AD-like symptoms partly by inhibiting neuroinflammation, which was related to the blocking of complement component 3. Our study provides theoretical support and experimental evidence for the future application of chanterelle-extracted polysaccharides in AD treatment, promoting the modern development of traditional medicines originating from natural polysaccharides., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Alzheimer's disease (AD) is prone to onset and progression under oxidative stress conditions. Hericium coralloides (HC) is an edible medicinal fungus that contains various nutrients and possesses antioxidant properties. In the present study, the nutritional composition and neuroprotective effects of HC on APP/PS1 mice were examined. Behavioral experiments showed that HC improved cognitive dysfunction in APP/PS1 mice. Immunohistochemical and Western blotting results showed that HC reduced the levels of p-tau and amyloid-β deposition in the brain. By altering the composition of the gut microbiota, HC promoted the growth of short-chain fatty acid-producing bacteria and suppressed the growth of Helicobacter . Metabolomic results showed that HC decreased D-glutamic acid and oxidized glutathione levels. In addition, HC reduced the levels of reactive oxygen species, enhanced the secretion of superoxide dismutase, catalase, and glutathione peroxidase, inhibited the production of malondialdehyde and 4-hydroxynonenal, and activated the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. Collectively, HC demonstrated antioxidant activity by activating Nrf2 signaling and regulating gut microbiota, further exerting neuroprotective effects. This study confirms that HC has the potential to be a clinically effective AD therapeutic agent and offers a theoretical justification for both the development and use of this fungus.

Verbascoside (VB) is a phenylethanoid glycoside extracted from the herbaceous plant Verbascum sinuatum and plays a neuroprotective role in Alzheimer's disease (AD). The goal of this study was to explore the neuroprotective mechanism of VB. Based on the proteomics analysis, immunohistochemistry, immunofluorescence, Western blot, and ELISA were utilized to explore the neuroprotective mechanism of VB in context of neuroinflammation in APP/PS1 mice, LPS-induced BV2 cells, and/or Aβ 1-42 -stimulated N2a cells. Proteomic analysis demonstrated that the neuroprotection of VB correlated closely to its anti-inflammatory effect. VB significantly blocked microglia and astrocyte against activation in brains of APP/PS1 mice, suppressed the generation of IL-1β as well as IL-6, and boosted that of IL-4, IL-10 and TGF-β in vivo, which were analogous to results acquired in vitro. Furthermore, VB effectively restrained the phosphorylation of IKKα+β, IκBα, and NF-κB-p65 in APP/PS1 mice; LPS-induced BV2 cells, and Aβ 1-42 -stimulated N2a cells and lowered the tendency of NF-κB-p65 translocation towards nucleus in vitro. These results demonstrate that the neuroprotective effect of VB correlates to the modulation of neuroinflammation via NF-κB-p65 pathway, making VB as a hopeful candidate drug for the prevention and treatment of AD.

Ferroptosis and neuroinflammation play crucial roles in Alzheimer's disease (AD) pathophysiology. Forsythoside A (FA), the main constituent of Forsythia suspensa (Thunb.) Vahl., possesses anti-inflammatory, antibacterial, antioxidant, and neuroprotective properties. The present study aimed to investigate the potential role of FA in AD neuropathology using male APP/PS1 double transgenic AD mice, Aβ 1-42 -exposed N2a cells, erastin-stimulated HT22 cells, and LPS-induced BV2 cells. FA treatment significantly improved mitochondrial function and inhibited lipid peroxidation in Aβ 1-42 -exposed N2a cells. In LPS-stimulated BV2 cells, FA treatment decreased the formation of the pro-inflammatory factors IL-6, IL-1β, and NO. In male APP/PS1 mice, FA treatment ameliorated memory and cognitive impairments and suppressed Aβ deposition and p-tau levels in the brain. Analyses using proteomics, immunohistochemistry, ELISA, and western blot revealed that FA treatment significantly augmented dopaminergic signaling, inhibited iron deposition and lipid peroxidation, prevented the activation of IKK/IκB/NF-κB signaling, reduced the secretion of pro-inflammatory factors, and promoted the production of anti-inflammatory factors in the brain. FA treatment exerted anti-ferroptosis and anti-neuroinflammatory effects in erastin-stimulated HT22 cells, and the Nrf2/GPX4 axis played a key role in these effects. Collectively, these results demonstrate the protective effects of FA and highlight its therapeutic potential as a drug component for AD treatment., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The purified polysaccharides from Hericium erinaceus fermented mycelium entitled with PHEB was analyzed and it was mainly composed of six glycosidic bonds. It has been confirmed to show the relieving activity against Alzheimer's Disease (AD)- just as behaviors of B6C3-Tg (APPswePSEN1d E9)/Nju double transgenic [Genotype: (Appswe)T, (Psen1) T] (APP/PS1) mice. Six-week PHEB administration significantly improved the cognitive behavior of mice. Brain injury, amyloid beta deposition and tau hyperphosphorylation were alleviated in PHEB-treated AD mice without changes in other tissues. PHEB alleviated the oxidative stress in brains of AD mice via regulation the Nrf2 and its downstream kinase, which further improved the cholinergic system function. Proteomics and bioinformatics analysis showed that the therapeutic effect of PHEB is achieved by regulating calcium homeostasis mediated by oxidative stress. Furthermore, PHEB regulated the CaMK II/IV to achieve the calcium homeostasis in brains; and ultimately to show the anti-AD property., (Copyright © 2021. Published by Elsevier B.V.)

Background: Endoplasmic reticulum (ER) stress is involved in the progression of Alzheimer's disease (AD). Verbascoside (VB), an active phenylethanoid glycoside that was first isolated from Verbascum sinuatum (the wavyleaf mullein), possesses anti-inflammatory, antioxidative, and anti-apoptotic effects. The purpose of this study was to elucidate the beneficial effects of VB in amyloid β (Aβ) 1-42 -damaged human glioma (U251) cells and in APPswe/PSEN1dE9 transgenic (APP/PS1) mice., Methods: U251 cells were co-incubated with 10 μM of Aβ 1-42 and treated with VB. The protective effects of VB were investigated by using 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide assay, flow cytometry, fluorescence staining, and transmission electron microscopy. APP/PS1 transgenic mice were treated for 6 weeks with VB. Learning and memory were evaluated using a Morris water maze test. Immunohistochemistry, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling, thioflavin-S staining, and proteomics analysis were performed to study the potential neuroprotective mechanism. Enzyme-linked immunosorbent assays and western blot were performed to analyze altered protein levels of brain lysates in APP/PS1 mice and/or Aβ 1-42 -damaged U251 cells., Results: In Aβ 1-42 -damaged U251 cells, VB significantly improved cell viability, inhibited apoptosis, reduced calcium accumulation and the intracellular concentrations of reactive oxygen species, and improved the morphology of mitochondria and ER. In APP/PS1 mice, 6-week administration of VB significantly improved memory and cognition. VB inhibited apoptosis, reduced the deposition of Aβ, reduced the formation of neurofibrillary tangles formed by hyperphosphorylated tau protein, and downregulated the expression levels of 4-hydroxynonenal and mesencephalic astrocyte-derived neurotrophic factor in the brains of APP/PS1 mice. Proteomics analysis of mouse hippocampus suggested that the neuroprotective effect of VB may be related to the reduction of ER stress. This was indicated by the fact that VB inhibited the three branches of the unfolded protein response, thereby attenuating ER stress and preventing apoptosis., Conclusions: The results confirmed that VB possesses significant neuroprotective effects, which are related to the reduction of ER stress. These findings support the status of VB as a potentially effective treatment for AD and warrant further research.

Improving mitochondrial dysfunction and inhibiting apoptosis has always been regarded as a treatment strategy for Alzheimer's disease (AD). Isoforsythiaside (IFY), a phenylethanoid glycoside isolated from the dried fruit of Forsythia suspensa , displays antioxidant activity. This study examined the neuroprotective effects of IFY and its underlying mechanisms. In the L-glutamate (L-Glu)-induced apoptosis of HT22 cells, IFY increased cell viability, inhibited mitochondrial apoptosis, and reduced the intracellular levels of reactive oxygen species (ROS), caspase-3, -8 and -9 after 3 h of pretreatment and 12-24 h of co-incubation. In the APPswe / PSEN1dE9 transgenic (APP/PS1) model, IFY reduced the anxiety of mice, improved their memory and cognitive ability, reduced the deposition of beta amyloid (Aβ) plaques in the brain, restrained the phosphorylation of the tau protein to form neurofibrillary tangles, inhibited the level of 4-hydroxynonenal in the brain, and improved phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway-related mitochondrial apoptosis. In Aβ 1-42 -induced U251 cells, IFY relieved the mitochondrial swelling, crest ruptures and increased their electron density after 3 h of pretreatment and 18-24 h of co-incubation. The improved cell viability and mitochondrial function after IFY incubation was blocked by the synthetic PI3K inhibitor LY294002. Taken together, these results suggest that IFY exerts a protective effect against AD by enhancing the expression levels of anti-apoptosis proteins and reducing the expression levels of pro-apoptosis proteins of B-cell lymphoma-2 (BCL-2) family members though activating the PI3K/AKT pathway.

By analyzing the L‑glutamic acid (L‑Glu)‑induced apoptosis of PC12 cells and an AlCl3 combined with D‑galactose (D‑gal)‑developed Alzheimer's disease (AD) mouse model, the protective effects of isoastilbin (IAB) against AD were systematically investigated in the present study. Pre‑incubation with IAB for 3 h prior to treatment with 25 mM L‑Glu decreased cell viability and inhibited apoptosis, suppressed the accumulation of intracellular reactive oxygen species, and restored mitochondrial membrane potential in PC12 cells induced by L‑Glu. In mice with AD, the reduced escape latency time in the water maze test, suppressed chronic movement in the center area of an open field test and enhanced ability to seek hidden food in a Y maze test indicated that abnormal behaviors had improved after 28 days of treatment with IAB. Furthermore, IAB reduced the deposition of amyloid β (Aβ) and the expression of phosphorylated‑Tau in the mouse brain and enhanced the serum levels of Aβ. IAB ameliorated the oxidative stress via modulating the levels of associated enzymes and improved the functioning of the central cholinergic system, as indicated by an increase in acetylcholine and choline acetyltransferase concentrations. The expression levels of acetylcholine esterase were reduced in the mouse brain in response to IAB pre‑treatment. In cells and brain tissue, IAB regulated the expression levels of pro‑ and anti‑apoptotic proteins and enhanced the nuclear levels of NF‑E2p45‑related factor 2 (Nrf2); subsequently, IAB further enhanced the expression of superoxide dismutase 1, catalase, and heme oxygenase‑1 and ‑2. The findings of the present study indicated that the protection of IAB against AD is at least partially associated with its antioxidation and anti‑apoptotic properties.

Due to its complex pathogenesis, the prevention and therapization of Alzheimer's disease (AD) remains a serious challenge. Crocin, the main compound isolated from Crocus sativus L., demonstrates various pharmacological activities including anti‑apoptotic properties. The present study investigated the neuroprotective effect of crocin and the underlying mechanisms. In l‑glutamate‑damaged HT22 cells, 3‑h crocin pretreatment strongly enhanced the HT22 cell viability, reduced the apoptotic rate, mitigated mitochondrial dysfunction, suppressed intracellular reactive oxygen species (ROS) accumulation and Ca2+ overload compared with untreated cells. Additionally, crocin significantly decreased the expression levels of Bax, Bad and cleaved caspase‑3 and increased the expression levels of B‑cell lymphoma‑extra large, phosphorylated (P‑) protein kinase B and P‑mammalian target of rapamycin compared with untreated cells. In mice with AD induced by d‑galactose and aluminum trichloride, crocin substantially improved the cognition and memory abilities of the mice as measured by their coordination of movement in an open field test, and reduced their escape time in the Morris water maze test compared with untreated mice. Biochemical analysis confirmed that crocin was able to reduce the Aβ1‑42 content in the mouse brains, increase the levels of glutathione peroxidase, superoxide dismutase, acetylcholine and choline acetyltransferase, and reduce the levels of ROS and acetylcholinesterase in the serum, cerebral cortex and hypothalamus compared with untreated mice. Immunohistochemical analysis demonstrated that crocin reduced Aβ1‑42 deposition in the hippocampus of the brains of treated mice compared with untreated mice. In conclusion, crocin demonstrates good prospects in the treatment of AD through the oxidative stress‑associated apoptosis signaling pathway.

This study explores the neuro-protective effects of Amanita caesarea polysaccharides (ACPS), obtained by 80% alcohol precipitation of water extract and purified using a DEAE-52 cellulose anion exchange column, related to antioxidant activity. A 3-h pre-treatment of ACPS prior to l‑glutamic acid (l‑Glu) co-exposure reversed the decreased cell viability, inhibited apoptosis, suppressed the accumulation of intracellular reactive oxygen species and restored mitochondrial membrane potential in HT22 cells. Compared to l‑Glu-exposed cells, ACPS enhanced the nuclear levels of NF-E2p45-related factor 2 (Nrf2), reduced the cytoplasmic levels of Nrf2 and cytochrome C, suppressed the expression of Kelch-like ECH-associated protein 1, and enhanced the expression of heme oxygenase‑1, superoxide dismutase 1 and cysteine ligase catalytic subunit. In a d‑galactose and aluminum trichloride Alzheimer's disease (AD) mouse model, 42-day administration of ACPS improved the abnormal behaviors. ACPS suppressed the deposition of β‑amyloid peptide in the brain and ameliorated oxidative stress via modulating the levels of related enzymes. ACPS improved the functioning of the central cholinergic system, as indicated by an increase in acetylcholine and choline acetyltransferase concentrations, and reduced acetylcholine esterase levels in the serum, hypothalamus and cerebral cortex. Our data suggest that ACPS may be a promising candidate for the treatment of AD., (Copyright © 2018. Published by Elsevier B.V.)

Evodiamine (Evo), a major alkaloid compound isolated from the dry unripened fruit of Evodia fructus, has a wide range of pharmacological activities. The present study sought to explore the neuroprotective effects of Evo in l-glutamate (l-Glu)-induced apoptosis of HT22 cells, and in a d-galactose and aluminum trichloride-developed Alzheimer’s disease (AD) mouse model. Evo significantly enhanced cell viability, inhibited the accumulation of reactive oxygen species, ameliorated mitochondrial function, increased the B-cell lymphoma-2 protein content, and inhibited the high expression levels of Bax, Bad, and cleaved-caspase-3 and -8 in l-Glu-induced HT22 cells. Evo also enhanced the phosphorylation activities of protein kinase B and the mammalian target of rapamycin in the l-Glu-induced HT22 cells. In the AD mouse model, Evo reduced the aimless and chaotic movements, reduced the time spent in the central area in the open field test, and decreased the escape latency time in the Morris water maze test. Evo reduced the deposition of amyloid beta 42 (Aβ42) in the brain, and increased the serum level of Aβ42, but showed no significant effects on Aβ40. In addition, six weeks of Evo administration significantly suppressed oxidative stress by modulating the related enzyme levels. In the central cholinergic system of AD mice, Evo significantly increased the serum levels of acetylcholine and choline acetyltransferase and decreased the level of acetylcholinesterase in the serum, hypothalamus, and brain. Our results provide experimental evidence that Evo can serve as a neuroprotective candidate for the prevention and/or treatment of neurodegenerative diseases.