RESUMEN
AIMS: Cognitive impairment is associated with reduced hippocampal neurogenesis; however, the causes of decreased hippocampal neurogenesis remain highly controversial. Here, we investigated the role of survivin in the modulation of hippocampal neurogenesis in AD. METHODS: To investigate the effect of survivin on neurogenesis in neural stem cells (NSCs), we treated mouse embryonic NSCs with a survivin inhibitor (YM155) and adeno-associated viral survivin (AAV-Survivin). To explore the potential role of survivin expression in AD, AAV9-Survivin or AAV9-GFP were injected into the dentate gyrus (DG) of hippocampus of 7-month-old wild-type and 5XFAD mice. Cognitive function was measured by the Y maze and Morris water maze. Neurogenesis was investigated by BrdU staining, immature, and mature neuron markers. RESULTS: Our results indicate that suppression of survivin expression resulted in decreased neurogenesis. Conversely, overexpression of survivin using AAV-Survivin restored neurogenesis in NSCs that had been suppressed by YM155 treatment. Furthermore, the expression level of survivin decreased in the 9-month-old 5XFAD compared with that in wild-type mice. AAV-Survivin-mediated overexpression of survivin in the DG in 5XFAD mice enhanced neurogenesis and cognitive function. CONCLUSION: Hippocampal neurogenesis can be enhanced by survivin overexpression, suggesting that survivin could serve as a promising therapeutic target for the treatment of AD.
Asunto(s)
Enfermedad de Alzheimer , Animales , Ratones , Enfermedad de Alzheimer/tratamiento farmacológico , Survivin/farmacología , Survivin/uso terapéutico , Hipocampo , Neurogénesis/fisiología , Cognición , Modelos Animales de Enfermedad , Ratones TransgénicosRESUMEN
Alzheimer's disease (AD) is an irreversible neurodegenerative disease characterized by memory and cognitive impairments. Neurogenesis, which is related to memory and cognitive function, is reduced in the brains of patients with AD. Therefore, enhancing neurogenesis is a potential therapeutic strategy for neurodegenerative diseases, including AD. Hesperidin (HSP), a bioflavonoid found primarily in citrus plants, has anti-inflammatory, antioxidant, and neuroprotective effects. The objective of this study was to determine the effects of HSP on neurogenesis in neural stem cells (NSCs) isolated from the brain of mouse embryos and five familial AD (5xFAD) mice. In NSCs, HSP significantly increased the proliferation of NSCs by activating adenosine monophosphate (AMP)-activated protein kinase (AMPK)/cAMP-response element-binding protein (CREB) signaling, but did not affect NSC differentiation into neurons and astrocytes. HSP administration restored neurogenesis in the hippocampus of 5xFAD mice via AMPK/brain-derived neurotrophic factor/tropomyosin receptor kinase B/CREB signaling, thereby decreasing amyloid-beta accumulation and ameliorating memory dysfunction. Collectively, these preclinical findings suggest that HSP is a promising candidate for the prevention and treatment of AD.
Asunto(s)
Enfermedad de Alzheimer , Hesperidina , Enfermedades Neurodegenerativas , Proteínas Quinasas Activadas por AMP/metabolismo , Enfermedad de Alzheimer/metabolismo , Animales , Modelos Animales de Enfermedad , Hesperidina/metabolismo , Hesperidina/farmacología , Hesperidina/uso terapéutico , Hipocampo/metabolismo , Ratones , Ratones Transgénicos , Enfermedades Neurodegenerativas/metabolismo , NeurogénesisRESUMEN
OBJECTIVES: Amyloid beta (Aß)-induced abnormal neuroinflammation is recognized as a major pathological factor of Alzheimer's disease (AD), which results in memory impairment. Inhibition of excessive neuroinflammation mediated by Aß is considered a promising strategy to ameliorate AD symptoms. To regulate the inflammatory response, nutritional and dietary supplements have been used for centuries. Based on this idea, we investigated whether MBN, a novel nutritional mixture including cassia bark, turmeric root, and ginkgo leaf, can prevent AD progression through neuroinflammatory regulation. METHODS: MBN (10, 30, or 100â µg/ml) and Aß1-42 monomer were incubated together, and the degree of Aß aggregation was measured using Thioflavin T assay. The effects of MBN on Aß pathology in vivo were evaluated by orally administering MBN (40â mg/kg/day for 16 weeks) to five familial AD (5xFAD) mice. RESULTS: We found that treatment with MBN inhibited Aß aggregation in vitro. Next, MBN treatment significantly inhibited the activation of microglia induced by aggregated Aß in 5xFAD mice. Caspase-1 activation, which plays an important role in the maturation of interleukin-1ß, was markedly reduced by MBN. We also found that oral administration of MBN in 5xFAD mice alleviated memory decline. Taken together, our findings demonstrate that MBN suppresses neuroinflammation by downregulating the caspase-1 expression, thereby ameliorating memory impairment in 5xFAD mice. DISCUSSION: Based on these results, we suggest that MBN may be a preventive and therapeutic supplement for AD through the regulation of neuroinflammation.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Caspasas/uso terapéutico , Modelos Animales de Enfermedad , Inflamasomas/uso terapéutico , Interleucina-1beta , Trastornos de la Memoria/patología , Trastornos de la Memoria/prevención & control , Ratones , Ratones Transgénicos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismoRESUMEN
Alzheimer's disease (AD), a type of dementia, is the most common neurodegenerative disease in the elderly. Neuroinflammation caused by deposition of amyloid ß (Aß) is one of the most important pathological causes in AD. The isoprenoid phytohormone abscisic acid (ABA) has recently been found in mammals and was shown to be an endogenous hormone, acting in stress conditions. Although ABA has been associated with anti-inflammatory effects and reduced cognitive impairment in several studies, the mechanisms of ABA in AD has not been ascertained clearly. To investigate the clearance of Aß and anti-inflammatory effects of ABA, we used quantitative real-time polymerase chain reaction and immunoassay. ABA treatment inhibited Aß deposition and neuroinflammation, thus resulting in improvement of memory impairment in 5xFAD mice. Interestingly, these effects were not associated with activation of peroxisome proliferator-activated receptor gamma, well known as a molecular target of ABA, but related with modulation of the LanC-like protein 2 (LANCL2), known as a receptor of ABA. Taken together, our results indicate that ABA reduced Aß deposition, neuroinflammation, and memory impairment, which is the most characteristic pathology of AD, via the upregulation of LANCL2. These data suggest that ABA might be a candidate for therapeutics for AD treatment.
Asunto(s)
Ácido Abscísico/farmacología , Proteínas de la Membrana/metabolismo , Trastornos de la Memoria/tratamiento farmacológico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Proteínas de Unión a Fosfato/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/patología , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/patología , Ratones , Ratones Mutantes , Ratones Transgénicos , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , PPAR gamma/metabolismo , Reguladores del Crecimiento de las Plantas/farmacología , Presenilina-1/genética , Presenilina-1/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Abnormal amyloid-ß (Aß) accumulation is the most significant feature of Alzheimer's disease (AD). Among the several secretases involved in the generation of Aß, ß-secretase (BACE1) is the first rate-limiting enzyme in Aß production that can be utilized to prevent the development of Aß-related pathologies. Cinnamon extract, used in traditional medicine, was shown to inhibit the aggregation of tau protein and Aß aggregation. However, the effect of trans-cinnamaldehyde (TCA), the main component of cinnamon, on Aß deposition is unknown. Five-month-old 5XFAD mice were treated with TCA for eight weeks. Seven-month-old 5XFAD mice were evaluated for cognitive and spatial memory function. Brain samples collected at the conclusion of the treatment were assessed by immunofluorescence and biochemical analyses. Additional in vivo experiments were conducted to elucidate the mechanisms underlying the effect of TCA in the role of Aß deposition. TCA treatment led to improvements in cognitive impairment and reduced Aß deposition in the brains of 5XFAD mice. Interestingly, the levels of BACE1 were decreased, whereas the mRNA and protein levels of three well-known regulators of BACE1, silent information regulator 1 (SIRT1), peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC1α), and PPARγ, were increased in TCA-treated 5XFAD mice. TCA led to an improvement in AD pathology by reducing BACE1 levels through the activation of the SIRT1-PGC1α-PPARγ pathway, suggesting that TCA might be a useful therapeutic approach in AD.
Asunto(s)
Acroleína/análogos & derivados , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , PPAR gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Sirtuina 1/metabolismo , Acroleína/farmacología , Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/patología , Animales , Antimutagênicos/farmacología , Femenino , Humanos , Masculino , Ratones , Ratones Transgénicos , PPAR gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Sirtuina 1/genéticaRESUMEN
Severe neuroinflammation is known as a main pathology of neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). In these diseases, excessive microglial activation is one of the main causes of inflammation in the central nervous system. Therefore, inhibition of activated microglia may be suggested as a treatment for neuroinflammatory diseases. Glibenclamide, known as a therapeutics for type 2 diabetes in clinical trials has been shown to be effective in the inhibiting inflammatory conditions of various diseases. However, studies on the effects of glibenclamide for improving AD pathologies are little known. In this study, we tested glibenclamide on microglial cell line BV2 and 5XFAD mice. We found that glibenclamide significantly inhibited nitric oxide (NO) at 10 µM and 40 µM in BV2 cells induced by lipopolysaccharide (LPS) stimulation. In addition, we confirmed that 40 µM of glibenclamide reduced pro-inflammatory cytokines and proteins in the LPS-stimulated microglial cells. The anti-inflammatory effect of glibenclamide was further tested in APP/PS1 transgenic mouse. Although further analysis would be needed to confirm whether glibenclamide affects behavioral performance, our data suggests that glibenclamide may be a therapeutic option for AD treatment.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Antiinflamatorios/farmacología , Encéfalo/efectos de los fármacos , Gliburida/farmacología , Microglía/efectos de los fármacos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/genética , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/fisiopatología , Línea Celular , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Mediadores de Inflamación/metabolismo , Masculino , Ratones Transgénicos , Microglía/metabolismo , Microglía/patología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Prueba del Laberinto Acuático de Morris/efectos de los fármacos , Mutación , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Presenilina-1/genéticaRESUMEN
BACKGROUND: Chronic neuroinflammation, aggressive amyloid beta (Aß) deposition, neuronal cell loss, and cognitive impairment are pathological presentations of Alzheimer's disease (AD). Therefore, resolution of neuroinflammation and inhibition of Aß-driven pathology have been suggested to be important strategies for AD therapy. Previous efforts to prevent AD progression have identified p38 mitogen-activated protein kinases (MAPKs) as a promising target for AD therapy. Recent studies showed pharmacological inhibition of p38α MAPK improved memory impairment in AD mouse models. METHODS: In this study, we used an AD mouse model, 5XFAD, to explore the therapeutic potential of NJK14047 which is a novel, selective p38α/ß MAPK inhibitor. The mice were injected with 2.5 mg/kg NJK14047 or vehicle every other day for 3 months. Morris water maze task and histological imaging analysis were performed. Protein and mRNA expression levels were measured using immunoblotting and qRT-PCR, respectively. In vitro studies were conducted to measure the cytotoxicity of microglia- and astrocyte-conditioned medium on primary neurons using the MTT assay and TUNEL assay. RESULTS: NJK14047 treatment downregulated phospho-p38 MAPK levels, decreased the amount of Aß deposits, and reduced spatial learning memory loss in 9-month-old 5XFAD mice. While the pro-inflammatory conditions were decreased, the expression of alternatively activated microglial markers and microglial phagocytic receptors was increased. Furthermore, NJK14047 treatment reduced the number of degenerating neurons labeled with Fluoro-Jade B in the brains of 5XFAD mice. The neuroprotective effect of NJK14047 was further confirmed by in vitro studies. CONCLUSION: Taken together, a selective p38α/ß MAPK inhibitor NJK14047 successfully showed therapeutic effects for AD in 5XFAD mice. Based on our data, p38 MAPK inhibition is a potential strategy for AD therapy, suggesting NJK14047 as one of the promising candidates for AD therapeutics targeting p38 MAPKs.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides , Animales , Disfunción Cognitiva/tratamiento farmacológico , Modelos Animales de Enfermedad , Ratones , Ratones Transgénicos , MicroglíaRESUMEN
Neuroinflammation is an immune response within the central nervous system against various proinflammatory stimuli. Abnormal activation of this response contributes to neurodegenerative diseases such as Parkinson disease, Alzheimer's disease, and Huntington disease. Therefore, pharmacologic modulation of abnormal neuroinflammation is thought to be a promising approach to amelioration of neurodegenerative diseases. In this study, we evaluated the synthetic flavone derivative 3',4'-dihydroxyflavone, investigating its anti-neuroinflammatory activity in BV2 microglial cells and in a mouse model. In BV2 microglial cells, 3',4'-dihydroxyflavone successfully inhibited production of chemokines such as nitric oxide and prostaglandin E2 and proinflammatory cytokines such as tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6 in BV2 microglia. It also inhibited phosphorylation of mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB activation. This indicates that the anti-inflammatory activities of 3',4'-dihydroxyflavone might be related to suppression of the proinflammatory MAPK and NF-κB signaling pathways. Similar anti-neuroinflammatory activities of the compound were observed in the mouse model. These findings suggest that 3',4'-dihydroxyflavone is a potential drug candidate for the treatment of microglia-related neuroinflammatory diseases.