Inonotus obliquus polysaccharides protect against Alzheimer's disease by regulating Nrf2 signaling and exerting antioxidative and antiapoptotic effects
Inonotus obliquus polysaccharide (IOPS) was initially separated and purified via precipitation from an aqueous extract with 80% alcohol, a DEAE-52 cellulose anion exchange column, and a Sephadex G-100 gel permeation chromatography system. IOPS was found to have a molecular weight of 111.9 kDa. In L-glutamic acid (L-Glu)-damaged HT22 cells, a 3-h pre-incubation with IOPS enhanced cell viability, inhibited apoptosis and caspase-3 activity, reduced the release of lactate dehydrogenase, restored the dissipated mitochondrial membrane potential, and suppressed the excess accumulation of intracellular reactive oxygen species. Compared with L-Glu-exposed cells, IOPS pre-treated cells exhibited reduced levels of Bcl-2 associated X protein (Bax) and Kelch-like ECH-associated protein 1 (Keap1) and enhanced levels of B-cell lymphoma-2 (Bcl-2), NF-E2p45-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), superoxide dismutase-1 (SOD-1), and cysteine ligase catalytic subunit. In amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice, an 8-week course of IOPS improved the pathological behaviors related to memory and cognition, reduced the deposition of β-amyloid peptides and neuronal fiber tangles induced by enhanced phosphor-Tau in the brain, and modulated the levels of anti- and pro-oxidative stress enzymes. Additionally, IOPS enhanced the expression levels of Nrf2 and its downstream proteins, including HO-1 and SOD-1, in the brains of APP/PS1 mice. The present study successfully demonstrated the protective effect of IOPS against AD and revealed the possible mechanism underlying the ability of IOPS to modulate oxidative stress, especially Nrf2 signaling, and mediate mitochondrial apoptosis.
Novel MicroRNA-455-3p and its protective effects against abnormal APP processing and amyloid beta toxicity in Alzheimer's disease
The purpose of our study is to understand the protective role of miR-455-3p against abnormal amyloid precursor protein (APP) processing, amyloid beta (Aβ) formation, defective mitochondrial biogenesis/dynamics and synaptic damage in AD progression. In-silico analysis of miR-455-3p has identified the APP gene as a putative target. Using mutant APP cells, miR-455-3p construct, biochemical and molecular assays, immunofluorescence and transmission electron microscopy (TEM) analyses, we studied the protective effects of miR-455-3p on - 1) APP regulation, amyloid beta (Aβ)(1-40) & (1-42) levels, mitochondrial biogenesis & dynamics; 3) synaptic activities and 4) cell viability & apoptosis. Our luciferase reporter assay confirmed the binding of miR-455-3p at the 3'UTR of APP gene. Immunoblot, sandwich ELISA and immunostaining analyses revealed that the reduced levels of the mutant APP, Aβ(1-40) & Aβ(1-42), and C99 by miR-455-3p. We also found the reduced levels of mRNA and proteins of mitochondrial biogenesis (PGC1α, NRF1, NRF2, and TFAM) and synaptic genes (synaptophysin and PSD95) in mutant APP cells; on the other hand, mutant APP cells that express miR-455-3p showed increased mRNA and protein levels of biogenesis and synaptic genes. Additionally, expression of mitochondrial fission proteins (DRP1 and FIS1) were decreased while the fusion proteins (OPA1, Mfn1 and Mfn2) were increased by miR-455-3p. Our TEM analysis showed a decrease in mitochondria number and an increase in the size of mitochondrial length in mutant APP cells transfected with miR-455-3p. Based on these observations, we cautiously conclude that miR-455-3p regulate APP processing and protective against mutant APP-induced mitochondrial and synaptic abnormalities in AD.
Roles of taurine in cognitive function of physiology, pathologies and toxication
Taurine is a key functional amino acid with many functions in the nervous system. The effects of taurine on cognitive function have aroused increasing attention. First, the fluctuations of taurine and its transporters are associated with cognitive impairments in physiology and pathology. This may help diagnose and treat cognitive impairment though mechanisms are not fully uncovered in existing studies. Then, taurine supplements in cognitive impairment of different physiologies, pathologies and toxicologies have been demonstrated to significantly improve and restore cognition in most cases. However, elevated taurine level in cerebrospinal fluid (CSF) by exogenous administration causes cognition retardations only in physiologically sensitive period between the perinatal to early postnatal period. In this review, taurine levels are summarized in different types of cognitive impairments. Subsequently, the effects of taurine supplements on cognitions in physiology, different pathologies and toxication of cognitive impairments (e.g. aging, Alzheimer' disease, streptozotocin (STZ)-induced brain damage, ischemia model, mental disorder, genetic diseases and cognitive injuries of pharmaceuticals and toxins) are analyzed. These data suggest that taurine can improve cognition function through multiple potential mechanisms (e.g. restoring functions of taurine transporters and γ-aminobutyric acid (GABA) A receptors subunit; mitigating neuroinflammation; up-regulating Nrf2 expression and antioxidant capacities; activating Akt/CREB/PGC1α pathway, and further enhancing mitochondria biogenesis, synaptic function and reducing oxidative stress; increasing neurogenesis and synaptic function by pERK; activating PKA pathway). However, more mechanisms still need explorations.
Supraphysiologic-dose anabolic-androgenic steroid use: A risk factor for dementia?
Supraphysiologic-dose anabolic-androgenic steroid (AAS) use is associated with physiologic, cognitive, and brain abnormalities similar to those found in people at risk for developing Alzheimer's Disease and its related dementias (AD/ADRD), which are associated with high brain β-amyloid (Aβ) and hyperphosphorylated tau (tau-P) protein levels. Supraphysiologic-dose AAS induces androgen abnormalities and excess oxidative stress, which have been linked to increased and decreased expression or activity of proteins that synthesize and eliminate, respectively, Aβ and tau-P. Aβ and tau-P accumulation may begin soon after initiating supraphysiologic-dose AAS use, which typically occurs in the early 20s, and their accumulation may be accelerated by other psychoactive substance use, which is common among non-medical AAS users. Accordingly, the widespread use of supraphysiologic-dose AAS may increase the numbers of people who develop dementia. Early diagnosis and correction of sex-steroid level abnormalities and excess oxidative stress could attenuate risk for developing AD/ADRD in supraphysiologic-dose AAS users, in people with other substance use disorders, and in people with low sex-steroid levels or excess oxidative stress associated with aging.
Molecular mechanisms underlying protective role of quercetin in attenuating Alzheimer's disease
Quercetin belongs to the flavonoids family, which is present in most of the plants including fruits, vegetables, green tea and even in red wine having antioxidant activities. It is available as a food supplement in the market and has physiological health effects. Quercetin has anti-inflammatory, anticancer and anti-prostate activities along with its beneficial effects on high cholesterol, kidney transplantation, asthma, diabetes, viral infections, pulmonary, schizophrenia and cardiovascular diseases. Quercetin possesses scavenging potential of hydroxyl radical (OH), hydrogen peroxide (HO), and superoxide anion (O). These reactive oxygen species (ROS) hampers lipid, protein, amino acids and deoxyribonucleic acid (DNA) processing leading to epigenetic alterations. Quercetin has the ability to combat these harmful effects. ROS plays a vital role in the progression of Alzheimer's disease (AD), and we propose that quercetin would be the best choice to overcome cellular and molecular signals in regulating normal physiological functions. However, data are not well documented regarding exact cellular mechanisms of quercetin. The neuroprotective effects of quercetin are mainly due to potential up- and/or down-regulation of cytokines via nuclear factor (erythroid-derived 2)-like 2 (Nrf2), Paraoxonase-2, c-Jun N-terminal kinase (JNK), Protein kinase C, Mitogen-activated protein kinase (MAPK) signalling cascades, and PI3K/Akt pathways. Therefore, the aim of the present review was to elaborate on the cellular and molecular mechanisms of the quercetin involved in the protection against AD.
MicroRNA-25 aggravates Aβ1-42-induced hippocampal neuron injury in Alzheimer's disease by downregulating KLF2 via the Nrf2 signaling pathway in a mouse model
Recently, numerous microRNAs (miRNAs) have been considered as key players in the regulation of neuronal processes. The purpose of the present study is to explore the effect of miR-25 on hippocampal neuron injury in Alzheimer's disease (AD) induced by amyloid β (Aβ) peptide fragment 1 to 42 (Aβ1-42) via Kruppel-like factor 2 (KLF2) through the nuclear factor-E2-related factor 2 (Nrf2) signaling pathway. A mouse model of AD was established through Aβ1-42 induction. The underlying regulatory mechanisms of miR-25 were analyzed through treatment of miR-25 mimics, miR-25 inhibitors, or small interfering RNA (siRNA) against KLF2 in hippocampal tissues and cells isolated from AD mice. The targeting relationship between miR-25 and KLF2 was predicted using a target prediction program and verified by luciferase activity determination. MTT assay was used to evaluate the proliferative ability and flow cytometry to detect cell cycle distribution and apoptosis. KLF2 was confirmed as a target gene of miR-25. When the mice were induced by Aβ1-42, proliferation was suppressed while apoptosis was promoted in hippocampal neurons as evidenced by lower levels of KLF2, Nrf2, haem oxygenase, glutathione S transferase α1, glutathione, thioredoxin, and B-cell lymphoma-2 along with higher bax level. However, such alternations could be reversed by treatment of miR-25 inhibitors. These findings indicate that miR-25 may inhibit hippocampal neuron proliferation while promoting apoptosis, thereby aggravating hippocampal neuron injury through downregulation of KLF2 via the Nrf2 signaling pathway.
Activation of Nrf2/ARE pathway alleviates the cognitive deficits in PS1V97L-Tg mouse model of Alzheimer's disease through modulation of oxidative stress
Oxidative stress refers to an imbalance between oxidative and antioxidative systems due to environmental factors. Although oxidative stress is implicated in the pathogenesis of Alzheimer's disease (AD), its precise role is not yet understood. We aimed to investigate the pathogenic mechanisms of the oxidative stress by using in vitro cultured neurons and in vivo AD models of PS1V97L-transgenic (Tg) mice. Our results showed that when oxidative stress became increasingly evident, the endogenous protective pathway of nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) decreased in 10-month-old PS1V97L-Tg mice. Activating the Nrf2/ARE pathway suppressed oxidative stress, decreased amyloid-β (Aβ), and improved the cognitive function of the PS1V97L-Tg mice. In contrast, blocking the Nrf2/ARE pathway augmented oxidative injury and decreased the cell viability of PS1V97L-Tg neurons. Our results highlight the role of the Nrf2/ARE pathway in regulating oxidative stress of the PS1V97L-Tg mice and may indicate a potential therapeutic avenue for AD treatment.
Artemisia amygdalina Upregulates Nrf2 and Protects Neurons Against Oxidative Stress in Alzheimer Disease
Alzheimer disease is a complex neurodegenerative disorder. It is the common form of dementia in elderly people. The etiology of this disease is multifactorial, pathologically it is accompanied with accumulation of amyloid beta and neurofibrillary tangles. Accumulation of amyloid beta and mitochondrial dysfunction leads to oxidative stress. In this study, neuroprotective effect of Artemisiaamygdalina against HO-induced death was studied in differentiated N2a and SH-SY5Ycells. Cells were treated with HO to induce toxicity which was attenuated by Artemisia amygdalina. The nuclear factor erythroid 2-related factor 2 (Nrf2) is an emerging regulator of cellular resistance to oxidants. It controls the basal and induced expression of antioxidant response element-dependent genes. Further, we demonstrated that Artemisia amygdalina protects neurons through upregulation of Nrf2 pathway. Moreover, reactive oxygen species and mitochondrial membrane potential loss formed by HO was attenuated by Artemisia amygdalina. Thus, Artemisia amygdalina may have the possibility to be a therapeutic agent for Alzheimer disease.
Protective roles of isoastilbin against Alzheimer's disease via Nrf2‑mediated antioxidation and anti‑apoptosis
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.
Edaravone reduces Aβ-induced oxidative damage in SH-SY5Y cells by activating the Nrf2/ARE signaling pathway
Edaravone potentially alleviates cognitive deficits in a mouse model of Alzheimer's disease (AD). However, the mechanism of edaravone in suppressing AD progression remains unclear. We aim to investigate the mechanism of edaravone in suppressing oxidative stress-mediated AD progression in vitro.
Hesperetin, a Citrus Flavonoid, Attenuates LPS-Induced Neuroinflammation, Apoptosis and Memory Impairments by Modulating TLR4/NF-κB Signaling
Glial activation and neuroinflammation play significant roles in apoptosis as well as in the development of cognitive and memory deficits. Neuroinflammation is also a critical feature in the pathogenesis of neurodegenerative disorders such as Alzheimer and Parkinson's diseases. Previously, hesperetin has been shown to be an effective antioxidant and anti-inflammatory agent. In the present study, in vivo and in vitro analyses were performed to evaluate the neuroprotective effects of hesperetin in lipopolysaccharide (LPS)-induced neuroinflammation, oxidative stress, neuronal apoptosis and memory impairments. Based on our findings, LPS treatment resulted in microglial activation and astrocytosis and elevated the expression of inflammatory mediators such as phosphorylated-Nuclear factor-κB (p-NF-κB), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) in the cortical and hippocampal regions and in BV2 cells. However, hesperetin cotreatment markedly reduced the expression of inflammatory cytokines by ameliorating Toll-like receptor-4 (TLR4)-mediated ionized calcium-binding adapter molecule 1/glial fibrillary acidic protein (Iba-1/GFAP) expression. Similarly, hesperetin attenuated LPS-induced generation of reactive oxygen species/lipid per oxidation (ROS/LPO) and improved the antioxidant protein level such as nuclear factor erythroid 2-related factor 2 (Nrf2) and Haem-oxygenase (HO-1) in the mouse brain. Additionally, hesperetin ameliorated cytotoxicity and ROS/LPO induced by LPS in HT-22 cells. Moreover, hesperetin rescued LPS-induced neuronal apoptosis by reducing the expression of phosphorylated-c-Jun N-terminal kinases (p-JNK), B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), and Caspase-3 protein and promoting the Bcl-2 protein level. Furthermore, hesperetin enhanced synaptic integrity, cognition, and memory processes by enhancing the phosphorylated-cAMP response element binding protein (p-CREB), postsynaptic density protein-95 (PSD-95), and Syntaxin. Overall, our preclinical study suggests that hesperetin conferred neuroprotection by regulating the TLR4/NF-κB signaling pathway against the detrimental effects of LPS.
Dimethyloxalylglycine preconditioning enhances protective effects of bone marrow-derived mesenchymal stem cells in Aβ- induced Alzheimer disease
Mesenchymal stem cell (MSC) transplantation therapy has been proposed as a promising approach for the treatment of neurodegenerative disease. Chemical and pharmacological preconditioning before transplantation could optimize the therapeutic properties of transplanted MSCs. In this study, we hypothesized that preconditioning treatment with a prolyl hydroxylase inhibitor, dimethyloxalylglycine (DMOG), will increase MSC efficacy and paracrine effects in an amyloid-β (Aβ)-injected Alzheimer rat model. MSCs were incubated in different concentrations of DMOG for 24 h. Cell viability, migration, and antioxidant capacity was assessed in DMOG-treated and non-treated MSCs before transplantation into Aβ-injected rats. In vitro analysis revealed that DMOG treatment increased cell viability, migration, and expression of CXCR4, CCR2, Nrf2, and HIF-1α in the MSCs. Our in vivo results show that DMOG preconditioning enhances a MSC-mediated rescue of learning and memory function in Aβ-injected rats. Furthermore, we found an increased level of BDNF and total antioxidant capacity in the hippocampus of Aβ-injected rats following transplantation of preconditioned relative to untreated MSCs. Our results suggest that preconditioning MSCs with DMOG before transplantation may enhance the efficacy of stem cell based therapy in neurodegenerative disease.
Anti-Inflammatory Activity of A Polyphenolic Extract from in In Vitro and In Vivo Models of Alzheimer's Disease
Alzheimer's disease (AD) is the most common neurodegenerative disorder and the primary form of dementia in the elderly. One of the main features of AD is the increase in amyloid-beta (Aβ) peptide production and aggregation, leading to oxidative stress, neuroinflammation and neurodegeneration. Polyphenols are well known for their antioxidant, anti-inflammatory and neuroprotective effects and have been proposed as possible therapeutic agents against AD. Here, we investigated the effects of a polyphenolic extract of (a plant belonging to the Brassicaceae family) on inflammatory response induced by Aβ. BV2 murine microglia cells treated with both Aβ peptide and extract showed a lower pro-inflammatory (, , ) and a higher anti-inflammatory (, , ) cytokine production compared to cells treated with Aβ only. The activation of the Nrf2-antioxidant response element signaling pathway in treated cells resulted in the upregulation of heme oxygenase-1 mRNA and in an increase of NAD(P)H:quinone oxidoreductase 1 activity. To establish whether the extract is also effective against Aβ-induced neurotoxicity in vivo, we evaluated its effect on the impaired climbing ability of AD Drosophila flies expressing human Aβ. Arabidopsis extract significantly restored the locomotor activity of these flies, thus confirming its neuroprotective effects also in vivo. These results point to a protective effect of the Arabidopsis extract in AD, and prompt its use as a model in studying the impact of complex mixtures derived from plant-based food on neurodegenerative diseases.
Ginsenoside Compound K Regulates Amyloid β via the Nrf2/Keap1 Signaling Pathway in Mice with Scopolamine Hydrobromide-Induced Memory Impairments
The objective of this study was to investigate the neuroprotective and antioxidant effects of ginsenoside compound K (CK) in a model of scopolamine hydrobromide-induced, memory-impaired mice. The role of CK in the regulation of amyloid β (Aβ) and its capacity to activate the Nrf2/Keap1 signaling pathway were also studied due to their translational relevance to Alzheimer's disease. The Morris water maze was used to assess spatial memory functions. Levels of superoxide dismutase, glutathione peroxidase, and malondialdehyde in brain tissues were tested. Cell morphology was detected by hematoxylin and eosin staining and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling assay. Immunohistochemistry and western blotting were used to determine expression levels of Nrf2/Keap1 signaling pathway-related factors and Aβ. Ginsenoside CK was found to enhance memory function, normalize neuronal morphology, decrease neuronal apoptosis, increase superoxide dismutase and glutathione peroxidase levels, reduce malondialdehyde levels, inhibit Aβ expression, and activate the Nrf2/Keap1 signaling pathway in scopolamine-exposed animals. Based on these results, we conclude that CK may improve memory function in scopolamine-injured mice by regulating Aβ aggregation and promoting the transduction of the Nrf2/Keap1 signaling pathway, thereby reducing oxidative damage to neurons and inhibiting neuronal apoptosis. This study suggests that CK may serve as a future preventative agent or treatment for Alzheimer's disease.
When safeguarding goes wrong: Impact of oxidative stress on protein homeostasis in health and neurodegenerative disorders
Cellular redox status is an established player in many different cellular functions. The buildup of oxidants within the cell is tightly regulated to maintain a balance between the positive and negative outcomes of cellular oxidants. Proteins are highly sensitive to oxidation, since modification can cause widespread unfolding and the formation of toxic aggregates. In response, cells have developed highly regulated systems that contribute to the maintenance of both the global redox status and protein homeostasis at large. Changes to these systems have been found to correlate with aging and age-related disorders, such as neurodegenerative pathologies. This raises intriguing questions as to the source of the imbalance in the redox and protein homeostasis systems, their interconnectivity, and their role in disease progression. Here we focus on the crosstalk between the redox and protein homeostasis systems in neurodegenerative diseases, specifically in Alzheimer's, Parkinson's, and ALS. We elaborate on some of the main players of the stress response systems, including the master regulators of oxidative stress and the heat shock response, Nrf2 and Hsf1, which are essential features of protein folding, and mediators of protein turnover. We illustrate the elegant mechanisms used by these components to provide an immediate response, including protein plasticity controlled by redox-sensing cysteines and the recruitment of naive proteins to the redox homeostasis array that act as chaperons in an ATP-independent manner.