Dietary Vitamin E Status Dictates Oxidative Stress Outcomes by Modulating Effects of Fish Oil Supplementation in Alzheimer Disease Model APP/PS1 Mice
Dong S, Huang X, Zhen J, Van Halm-Lutterodt N, Wang J, Zhou C and Yuan L
Quite a number of studies have examined the effects of fish oil supplementation on cognitive performance in different transgenic animal models of Alzheimer's disease (AD). However, inconsistent and controversial outcomes have been derived from these experiments. In order to investigate whether the beneficial effect of fish oil supplementation on cognition was dietary VE status associated, fish oil dietary intervention was carried out in transgenic APP/PS1 (APP/PS1) mice. Control mice (C57BL/6J mice) were fed a normal control diet. APP/PS1 mice were assigned to a normal control diet group and low VE diet + fish oil supplement, normal VE diet + fish oil supplement, and high VE diet + fish oil supplement groups, respectively. After 7 months of dietary intervention, we found that fish oil supplementation improved behavioral performance, alleviated brain beta-amyloid (Aβ) plaque burden, and attenuated the oxidative stress in APP/PS1 mice by increasing cortical GSH content and total antioxidant capacity, as well as by decreasing MDA level. Fish oil treatment increased cortical n-3 PUFA concentration and decreased n-6/n-3 PUFA ratio in APP/PS1 mice. Fatty acid transporters, Nrf2 and downstream targets involved in cortical and hippocampal antioxidant system were also modulated by fish oil-supplemented diet. Our data demonstrate that fish oil supplementation exerts an enhanced modulatory effect on the antioxidant system and fatty acid concentrations in APP/PS1 mice fed on lowly or averagely concentrated level of VE-containing diet than in mice fed with VE-rich diet. The current data do support previous findings that already dictate the beneficial effect of n-3 PUFAs on cognitive function. Moreover, the cognition promoting effects of n-3 PUFAs may be dietary VE status related.
Kynurenic Acid Restores Nrf2 Levels and Prevents Quinolinic Acid-Induced Toxicity in Rat Striatal Slices
Ferreira FS, Biasibetti-Brendler H, Pierozan P, Schmitz F, Bertó CG, Prezzi CA, Manfredini V and Wyse ATS
Kynurenic acid (KYNA) and quinolinic acid (QUIN) are metabolites produced in the degradation of tryptophan and have important neurological activities. KYNA/QUIN ratio changes are known to be associated with central nervous system disorders, such Alzheimer, Parkinson, and Huntington diseases. In the present study, we investigate the ability of KYNA in prevent the first events preceding QUIN-induced neurodegeneration in striatal slices of rat. We evaluated the protective effect of KYNA on oxidative status (reactive oxygen species production, antioxidant enzymes activities, lipid peroxidation, nitrite levels, protein and DNA damage, and iNOS immunocontent), mitochondrial function (mitochondrial mass, membrane potential, and respiratory chain enzymes), and Na,K-ATPase in striatal slices of rats treated with QUIN. Since QUIN alters the levels of Nrf2, we evaluated the influence of KYNA protection on this parameter. Striatal slices from 30-day-old Wistar rats were preincubated with KYNA (100 μM) for 15 min, followed by incubation with 100-μM QUIN for 30 min. Results showed that KYNA prevented the increase of ROS production caused by QUIN and restored antioxidant enzyme activities and the protein and lipid damage, as well as the Nrf2 levels. KYNA also prevented the effects of QUIN on mitochondrial mass and mitochondrial membrane potential, as well as the decrease in the activities of complex II, SDH, and Na,K-ATPase. We suggest that KYNA prevents changes in Nrf2 levels, oxidative imbalance, and mitochondrial dysfunction caused by QUIN in striatal slices. This study elucidates some of the protective effects of KYNA against the damage caused by QUIN toxicity.
Streptocyclinones A and B ameliorate Alzheimer's disease pathological processes in vitro
Alvariño R, Alonso E, Lacret R, Oves-Costales D, Genilloud O, Reyes F, Alfonso A and Botana LM
Alzheimer's disease (AD) is a pathology characterized by the abnormal accumulation of amyloid-beta (Aβ) and hyperphosphorylated tau. Oxidative stress and neuroinflammation are also strongly related to this disease. The ability of two new glycosylated angucyclinones, streptocyclinones A and B (1 and 2), isolated from Streptomyces sp to improve AD hallmarks was evaluated. Compounds were able to protect SH-SY5Y neuroblastoma cells from HO-induced oxidative injury by activating the nuclear factor E2-related factor (Nrf2). Their capacity to modulate neuroinflammation was tested in lipopolysaccharide-activated BV2 microglial cells. Compounds reduced the release of pro-inflammatory factors, inhibited the activation of NFκB and mitogen activated kinases (MAPK), and induced the translocation of Nrf2 to the nucleus of microglial cells. A trans-well co-culture was established to determine the effect of microglia treated with streptocyclinones on the survival of SH-SY5Y cells. The cell viability of neuroblastoma cells increased when the compounds were added to BV2 cells. SH-SY5Y-TMHT441 cells were used to determine the effect of compounds on tau phosphorylation. Both compounds reduced tau hyperphophorylation by targeting MAPK kinases. Moreover, streptocyclinone B (2) was able to inhibit the activity of β-secretase 1 and decrease the release of reactive oxygen species in BV2 cells stimulated with Aβ. With the same co-culture trans-well system, the treatment of Aβ-stimulated microglia with compound 2 augmented the viability of SH-SY5Y-TMHT441 cells. The results presented in this work provide evidences of the multitarget activities displayed by these new Streptomyces compounds, making them good candidates for further studies in the treatment of AD.
Mini-GAGR, an intranasally applied polysaccharide, activates the neuronal Nrf2-mediated antioxidant defense system
Murphy KE, Llewellyn K, Wakser S, Pontasch J, Samanich N, Flemer M, Hensley K, Kim DS and Park JJ
Oxidative stress triggers and exacerbates neurodegeneration in Alzheimer's disease (AD). Various antioxidants reduce oxidative stress, but these agents have little efficacy due to poor blood-brain barrier (BBB) permeability. Additionally, single-modal antioxidants are easily overwhelmed by global oxidative stress. Activating nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) and its downstream antioxidant system are considered very effective for reducing global oxidative stress. Thus far, only a few BBB-permeable agents activate the Nrf2-dependent antioxidant system. Here, we discovered a BBB-bypassing Nrf2-activating polysaccharide that may attenuate AD pathogenesis. Mini-GAGR, a 0.7 kD cleavage product of low-acyl gellan gum, increased the levels and activities of Nrf2-dependent antioxidant enzymes, decreased reactive oxygen species (ROS) under oxidative stress in mouse cortical neurons, and robustly protected mitochondria from oxidative insults. Moreover, mini-GAGR increased the nuclear localization and transcriptional activity of Nrf2 similarly to known Nrf2 activators. Mechanistically, mini-GAGR increased the dissociation of Nrf2 from its inhibitor, Kelch-like ECH-associated protein 1 (Keap1) and induced phosphorylation and nuclear translocation of Nrf2 in a protein kinase C (PKC)- and fibroblast growth factor receptor (FGFR1)-dependent manner. Finally, 20-day intranasal treatment of 3xTg-AD mice with 100 nmole mini-GAGR increased nuclear p-Nrf2 and growth-associated protein 43 (GAP43) levels in hippocampal neurons, reduced p-tau and amyloid-β (Aβ) peptide-stained neurons, and improved memory. The BBB-bypassing Nrf2-activating polysaccharide reported here may be effective in reducing oxidative stress and neurodegeneration in AD.
Protective roles of Amanita caesarea polysaccharides against Alzheimer's disease via Nrf2 pathway
Li Z, Chen X, Zhang Y, Liu X, Wang C, Teng L and Wang D
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.
The cargo receptor SQSTM1 ameliorates neurofibrillary tangle pathology and spreading through selective targeting of pathological MAPT (microtubule associated protein tau)
Xu Y, Zhang S and Zheng H
Accumulating evidence suggests that misfolded MAPT (microtubule associated protein tau), the main component of neurofibrillary tangles in tauopathies, is subject to degradation by the autophagy-lysosomal pathway. Selective autophagy is a subtype of macroautophagy that requires cargo receptors, such as OPTN (optineurin) or SQSTM1, to recognize specific targets for their sequestration within the autophagosome and their eventual degradation by the lysosome, although their roles in targeting distinct MAPT species have not been fully investigated. Using cargo receptor knockout cell lines and a seeding-based cellular assay in which neurofibrillary tangle pathology can be modeled in vitro, we reveal that while OPTN primarily targets soluble MAPT expressed in physiological conditions, SQSTM1 predominantly degrades insoluble but not soluble mutant MAPT. Endogenous SQSTM1 colocalizes with misfolded and aggregated MAPT species in vitro and in vivo, and both this colocalization and its function in MAPT clearance require both the LC3-interacting region (LIR) motif and also the PB1 self-polymerization domain of SQSTM1. Further, pathogenic MAPT accumulation reduces basal macroautophagy/autophagy in vitro and is associated with a compensatory upregulation of the lysosomal pathway in vivo. Finally, increased expression of SQSTM1 in MAPT transgenic mouse brains ameliorates MAPT pathology and prion-like spreading. Our results uncover distinct properties of selective autophagy receptors in targeting different MAPT species, implicate compromised autophagy as a potential underlying factor in mutant MAPT deposition, and demonstrate a potent and specific role of SQSTM1 in targeted clearance of pathogenic MAPT, through which it blocks neurofibrillary tangle accumulation and pathological spreading. Abbreviations: AAV: adeno-associated virus; AD: Alzheimer disease; ALP: autophagy-lysosomal pathway; ALS: amyotrophic lateral sclerosis; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; FTD: frontotemporal dementias; HD: Huntington disease; HTT: huntingtin; LIR: LC3-interacting region; NBR1: autophagy cargo receptor; NFE2L2/Nrf2: nuclear factor, erythroid derived 2, like 2; NFTs: neurofibrillary tangles; MAPT: microtubule associated protein tau; OPTN: optineurin; p-MAPT: hyperphosphorylated MAPT; PFA: paraformaldehyde; TARDBP/TDP-43: TAR DNA binding protein; TAX1BP1 Tax1: binding protein 1; ThioS: thioflavin-S; UBA: ubiquitin-associated.
Deficiency in the transcription factor NRF2 worsens inflammatory parameters in a mouse model with combined tauopathy and amyloidopathy
Rojo AI, Pajares M, García-Yagüe AJ, Buendia I, Van Leuven F, Yamamoto M, López MG and Cuadrado A
Chronic neuroinflammation is a hallmark of the onset and progression of brain proteinopathies such as Alzheimer disease (AD) and it is suspected to participate in the neurodegenerative process. Transcription factor NRF2, a master regulator of redox homeostasis, controls acute inflammation but its relevance in low-grade chronic inflammation of AD is inconclusive due to lack of good mouse models. We have addressed this question in a transgenic mouse that combines amyloidopathy and tauopathy with either wild type (AT-NRF2-WT) or NRF2-deficiency (AT-NRF2-KO). AT-NRF2-WT mice died prematurely, at around 14 months of age, due to motor deficits and a terminal spinal deformity but AT-NRF2-KO mice died roughly 2 months earlier. NRF2-deficiency correlated with exacerbated astrogliosis and microgliosis, as determined by an increase in GFAP, IBA1 and CD11b levels. The immunomodulatory molecule dimethyl fumarate (DMF), a drug already used for the treatment of multiple sclerosis whose main target is accepted to be NRF2, was tested in this preclinical model. Daily oral gavage of DMF during six weeks reduced glial and inflammatory markers and improved cognition and motor complications in the AT-NRF2-WT mice compared with the vehicle-treated animals. This study demonstrates the relevance of the inflammatory response in experimental AD, tightly regulated by NRF2 activity, and provides a new strategy to fight AD.
Berberine: Pathways to protect neurons
Lin X and Zhang N
Berberine, an isoquinoline alkaloid, is demonstrated to have a variety of pharmacologic effects. Widely used as nonprescription drug for diarrhea, berberine has also broadened its applications in therapies of cardiovascular diseases, diabetes mellitus, tumor, and so forth. However, researches about berberine's protective effects on nervous system are still so insufficient that clinical uses cannot popularize and underlying molecules mechanisms are confused and incomplete. Well-known pathways such as Pl3K/Akt/Bcl-2 pathway, Nrf2/HO-1 pathway, and MAPK signaling pathway help berberine to protect neurons through antiapoptotic, antioxidative, and anti-inflammatory activities. New hypotheses have been raised consistently to explore more possible ways of berberine preventing nerves from injuries as attention on its neuroprotective properties is increasing. Therefore, this review is trying to analyze these mechanisms, which actually play roles in neuronal disease models such as brain ischemia, Alzheimer's disease, and experimental autoimmune encephalomyelitis. Much more understanding about how berberine mediates these pathways provides novel insights into the clinical treatment of neurological disorders.
Heme Oxygenase 1 in the Nervous System: Does It Favor Neuronal Cell Survival or Induce Neurodegeneration?
Nitti M, Piras S, Brondolo L, Marinari UM, Pronzato MA and Furfaro AL
Heme oxygenase 1 (HO-1) up-regulation is recognized as a pivotal mechanism of cell adaptation to stress. Under control of different transcription factors but with a prominent role played by Nrf2, HO-1 induction is crucial also in nervous system response to damage. However, several lines of evidence have highlighted that HO-1 expression is associated to neuronal damage and neurodegeneration especially in Alzheimer's and Parkinson's diseases. In this review, we summarize the current literature regarding the role of HO-1 in nervous system pointing out different molecular mechanisms possibly responsible for HO-1 up-regulation in nervous system homeostasis and neurodegeneration.
CART peptide activates the Nrf2/HO-1 antioxidant pathway and protects hippocampal neurons in a rat model of Alzheimer's disease
Jiao W, Wang Y, Kong L, Ou-Yang T, Meng Q, Fu Q and Hu Z
The accumulation of amyloid-beta (Aβ) and oxidative stress damage in the brain are recognized as early features of Alzheimer's disease (AD). The cocaine- and amphetamine-regulated transcript (CART) peptide may possibly play an antioxidative role in neurons. The aim of this study was to investigate the potential antioxidant mechanism of CART peptide in a rat model of AD. We microinjected of Aβ (2μl/4μg/hemisphere) into rat hippocampus to set a rat model of AD. A pre-microinjection of CART peptide (1μl/0.02μg/hemisphere) into rat hippocampus was administered for five consecutive days before Aβ treatment. We found that Aβ microinjection led to reduction of endogenous CART level in rat hippocampus. CART pretreatment improved the spatial memory and locomotor ability of AD rats. CART peptide decreased the Aβ and Aβ production-associated enzyme BACE1 levels. Moreover, CART peptide attenuated the oxidative stress damage with a concrete manifestation of increased MDA as well as decreased T-SOD, GSH and ATP levels in the hippocampus of Aβ-treated rat, which may be causatively implicated the activating of Nrf2/HO-1 signaling pathway. Furthermore, CART peptide attenuated neuronal apoptosis with decreased Bax, caspase-9 and caspase-3 levels and increased Bcl-2 level in rat hippocampus. Our results therefore indicate that CART peptide could serve as an antioxidant in early therapy for AD.
Pyridoxine exerts antioxidant effects in cell model of Alzheimer's disease via the Nrf-2/HO-1 pathway
Li C, Wang R, Hu C, Wang H, Ma Q, Chen S and He Y
Pyridoxine is a water- soluble pyridine derivative. The effect of pyridoxine in cell models of Alzheimer's disease (AD), and the potential mechanisms involved, are not fully understood. In this study, the anti-AD effects of pyridoxine were studied in an AD cell model using a combination of techniques viz MTT assay, western blotting and assays for reactive oxygen species (ROS). Assays were also carried out to determine the mechanism underlying the antioxidant effects of pyridoxine. The results obtained revealed that pyridoxine exerted a protective potential against AD, attenuated ROS levels, decreased the expressions of cytoplasmic Nrf2, and upregulated whole-cell HO-1 expression. These results suggest that the anti-AD effect of pyridoxine may be attributed to its anti-oxidant property elicited via stimulation of the Nrf2/HO-1 pathway.
Rosmarinic acid attenuates β-amyloid-induced oxidative stress via Akt/GSK-3β/Fyn-mediated Nrf2 activation in PC12 cells
Rong H, Liang Y and Niu Y
Oxidative stress is an important pathogenic factor in Alzheimer's disease (AD). Recently, nuclear factor E2-related factor 2 (Nrf2) has emerged as a master regulator for the endogenous antioxidant response, and thus represents an attractive therapeutic target against AD. The aim of this study is to test the hypothesis that rosmarinic acid (RosA) attenuates amyloid-β (Aβ)-evoked oxidative stress through activating Nrf2-inducible cellular antioxidant defense system. Here, we reported that RosA attenuated Aβ-induced cellular reactive oxygen species (ROS) generation and lipid hydroperoxides (LPO). Interestingly, knockdown of Nrf2 by plasmid-based short hairpin RNA (shRNA) abrogated, at least in part, RosA-mediated neuroprotection in Aβ-challenged PC12 cells. Mechanistically, RosA enhanced the nuclear translocation of Nrf2 and binding to antioxidant response element (ARE) core element but did not induced Nrf2 transcription. Simultaneously, RosA induced a set of Nrf2 downstream target genes encoding phase-II antioxidant enzymes. Furthermore, RosA enhanced protein kinase B (Akt) phosphorylation, glycogen synthase kinase-3β (GSK-3β) phosphorylation at Ser9, and Fyn phosphorylation. Noteworthy, pharmacological inhibition or gene knockdown studies demonstrated that Akt locate upstream of GSK-3β and regulate Nrf2 through Fyn in the context of PC12 cells pre-incubated with RosA following exposed to Aβ. Conversely, the antioxidant effects of RosA could be blocked by Akt inhibitors LY294002, GSK-3β inhibitor LiCl, Nrf2 shRNA, or Fyn shRNA in Aβ-challenged PC12 cells. Consequently, the antioxidant effects of RosA are mediated predominantly by Akt/GSK-3β/Fyn pathway through increased activity of Nrf2. These results suggest, although do not prove, that RosA can be a promising candidate for neuroprotective treatment of AD.
Dl-3-n-Butylphthalide Inhibits NLRP3 Inflammasome and Mitigates Alzheimer's-Like Pathology via Nrf2-TXNIP-TrX Axis
Wang CY, Xu Y, Wang X, Guo C, Wang T and Wang ZY
Oxidative stress and neuroinflammation play important roles in the pathology of Alzheimer's disease (AD). Thioredoxin-interacting protein (TXNIP), an endogenous inhibitor of antioxidant thioredoxin, is suspected to be an important modulator of oxidative stress and inflammation. However, the underlying mechanism involved in the abnormal homeostasis of TXNIP-thioredoxin (TrX) in AD pathogenesis remains unclear.
Anti-Oxidant and Anti-Inflammatory Activity of Ketogenic Diet: New Perspectives for Neuroprotection in Alzheimer's Disease
Pinto A, Bonucci A, Maggi E, Corsi M and Businaro R
The ketogenic diet, originally developed for the treatment of epilepsy in non-responder children, is spreading to be used in the treatment of many diseases, including Alzheimer’s disease. The main activity of the ketogenic diet has been related to improved mitochondrial function and decreased oxidative stress. B-Hydroxybutyrate, the most studied ketone body, has been shown to reduce the production of reactive oxygen species (ROS), improving mitochondrial respiration: it stimulates the cellular endogenous antioxidant system with the activation of nuclear factor erythroid-derived 2-related factor 2 (Nrf2), it modulates the ratio between the oxidized and reduced forms of nicotinamide adenine dinucleotide (NAD⁺/NADH) and it increases the efficiency of electron transport chain through the expression of uncoupling proteins. Furthermore, the ketogenic diet performs anti-inflammatory activity by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) activation and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome as well as inhibiting histone deacetylases (HDACs), improving memory encoding. The underlying mechanisms and the perspectives for the treatment of Alzheimer’s disease are discussed.
Evaluation of antioxidant and neuroprotective activities of (L.) using the model
Thabit S, Handoussa H, Roxo M, El Sayed NS, Cestari de Azevedo B and Wink M
(L.) (Fabaceae) is a medicinal plant from tropical Asia. It is known for its marked antioxidant activity, which is attributed to its high phenolic content. The present study aims at testing both the antioxidant and neuroprotective effects of a hydroalcoholic extract from the aerial parts of using the model, which is widely used in this context.

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