Lithium chloride reduced the level of oxidative stress in brains and serums of APP/PS1 double transgenic mice via the regulation of GSK3β/Nrf2/HO-1 pathway
The aim of this study is to investigate whether lithium chloride (LiCl) can regulate glycogen synthase kinase-3β (GSK3β)/nuclear factor E2 related factor（Nrf2）/heme oxygenase-1 (HO-1) pathway to reduce the injury of oxidative stress in APP/PS1 double transgenic mice. The APP/PS1 double transgenic and wild-type (WT) mice were divided randomly into 4 groups, i.e., WT, WT + LiCl (LiCl 100 mg/kg by gavage once daily), the transgenic + LiCl and the transgenic groups. The expressions of phosphor-GSK3β (ser9), Nrf2 and HO-1 at protein levels were detected by Western blotting. The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and the content of malondialdehyde (MDA) were measured by related detection kits. Nissl bodies in different brain regions were examined by Nissl staining. The decreased protein levels of phosphor-GSK3β (ser9), Nrf2 and HO-1, the declined activities of SOD and GSH-Px, the increased content of MDA and the decreased Nissl bodies in neurons were observed in the brains or serums of APP/PS1 mice as compared with WT. The treatment with LiCl attenuated these changes in the levels of GSK3β/Nrf2/HO-1 pathway and oxidative stress as well as Nissl bodies induced by APP/PS1 mutation. LiCl reversed the declined activities of SOD and GSH-Px and the increased content of MDA as well as the decreased Nissl bodies in neurons in the brains or serums of APP/PS1 mice, the mechanism of which may be involved in the down-regulation of the activity of GSK3β and consequently enhances the expressions of Nrf2 and HO-1.
NF-E2-related factor 2 activation boosts antioxidant defenses and ameliorates inflammatory and amyloid properties in human Presenilin-1 mutated Alzheimer's disease astrocytes
Alzheimer's disease (AD) is a common dementia affecting a vast number of individuals and significantly impairing quality of life. Despite extensive research in animal models and numerous promising treatment trials, there is still no curative treatment for AD. Astrocytes, the most common cell type of the central nervous system, have been shown to play a role in the major AD pathologies, including accumulation of amyloid plaques, neuroinflammation, and oxidative stress. Here, we show that inflammatory stimulation leads to metabolic activation of human astrocytes and reduces amyloid secretion. On the other hand, the activation of oxidative metabolism leads to increased reactive oxygen species production especially in AD astrocytes. While healthy astrocytes increase glutathione (GSH) release to protect the cells, Presenilin-1-mutated AD patient astrocytes do not. Thus, chronic inflammation is likely to induce oxidative damage in AD astrocytes. Activation of NRF2, the major regulator of cellular antioxidant defenses, encoded by the NFE2L2 gene, poses several beneficial effects on AD astrocytes. We report here that the activation of NRF2 pathway reduces amyloid secretion, normalizes cytokine release, and increases GSH secretion in AD astrocytes. NRF2 induction also activates the metabolism of astrocytes and increases the utilization of glycolysis. Taken together, targeting NRF2 in astrocytes could be a potent therapeutic strategy in 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.
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.
Activation of Nrf2 signaling by sitagliptin and quercetin combination against β-amyloid induced Alzheimer's disease in rats
The objective of this study was to evaluate the neuroprotective effect of sitagliptin (Sita), quercetin (QCR) and its combination in β-amyloid (Aβ) induced Alzheimer's disease (AD). Male Sprague-Dawley rats, weighing between 220 and 280 g were used for experiment. Rats were divided into 5 groups (n = 10) and the groups were as follows: (a) Sham control; (b) Aβ injected; (c) Aβ injected + Sita 100; (d) Aβ injected + QCR 100; and (e) Aβ injected + Sita 100 + QCR 100. Cognitive performance was observed by the Morris water maze (MWM), biochemical markers, for example, MDA, SOD, CAT, GSH, Aβ1-42 level, Nrf2/HO-1 expression and histopathological study of rat brain were estimated. Pretreatment with Sita, QCR and their combination showed a significant increase in escape latency in particular MWM cognitive model. Further co-administration of sita and QCR significantly reduced Aβ1-42 level when compared with individual treatment. Biochemical markers, for example, increased SOD, CAT and GSH, decreased MDA were seen, and histopathological studies revealed the reversal of neuronal damage in the treatment group. Additionally, Nrf2/HO-1 pathway in rat's brain was significantly increased by Sita, QCR and their combination. Pretreatment with QCR potentiates the action of Sita in Aβ induced AD in rats. The improved cognitive memory could be because of the synergistic effect of the drugs by decreasing Aβ1-42 level, antioxidant activity and increased expression of Nrf2/HO-1 in rat brain.
Exploring the bi-directional relationship between autophagy and Alzheimer's disease
Alzheimer's disease (AD) is characterized by β-amyloid (Aβ) deposition and Tau phosphorylation, in which its pathogenesis has not been cleared so far. The metabolism of Aβ and Tau is critically affected by the autophagy. Abnormal autophagy is thought to be involved in the pathogenesis of AD, regulating autophagy may become a new strategy for AD treatment. In the early stage of AD, the presence of Aβ and Tau can induce autophagy to promote their clearance by means of mTOR-dependent and independent manners. As AD progress, the autophagy goes aberrant. As a result, Aβ and Tau generate continually, which aggravates both autophagy dysfunction and AD. Besides, several related genes and proteins of AD can also adapt autophagy to make an effect on the AD development. There seems to be a bi-directional relationship between AD pathology and autophagy. At present, this article reviews this relationship from these aspects: (a) the signaling pathways of regulating autophagy; (b) the relationships between the autophagy and the processing of Aβ; (c) Aβ and Tau cause autophagy dysfunction; (d) normal autophagy promotes the clearance of Aβ and Tau; (e) the relationships between the autophagy and both genes and proteins related to AD: TFEB, miRNAs, Beclin-1, Presenilin, and Nrf2; and (f) the small molecules regulating autophagy on AD therapy. All of the above may help to further elucidate the pathogenesis of AD and provide a theoretical basis for clinical treatment of 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.
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.
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.
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.
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.
Effects of Resveratrol on the Mechanisms of Antioxidants and Estrogen in Alzheimer's Disease
To observe the effects of resveratrol (Res) on the antioxidative function and estrogen level in an Alzheimer's disease (AD) mouse model.
Amyloid-β Aggregation Inhibitory and Neuroprotective Effects of Xanthohumol and its Derivatives for Alzheimer's Diseases
Xanthohumol has been reported to have cytoprotection through activation of Nrf2-ARE signaling pathway and; it has capability of scavenging free radicals, suggesting its potential for the prevention of neurodegeneration. However, the bio-incompatibility and blood-brain barrier impermeability of xanthohumol hindered its in vivo efficacy potential for treating Alzheimer's disease (AD).