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1.
Int J Mol Sci ; 22(19)2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34638752

RESUMO

Alzheimer's disease (AD) is characterized by the deposition of ß-amyloid peptide (Aß). There are currently no drugs that can successfully treat this disease. This study first explored the anti-inflammatory activity of seven components isolated from Antrodia cinnamonmea in BV2 cells and selected EK100 and antrodin C for in vivo research. APPswe/PS1dE9 mice were treated with EK100 and antrodin C for one month to evaluate the effect of these reagents on AD-like pathology by nesting behavior, immunohistochemistry, and immunoblotting. Ergosterol and ibuprofen were used as control. EK100 and antrodin C improved the nesting behavior of mice, reduced the number and burden of amyloid plaques, reduced the activation of glial cells, and promoted the perivascular deposition of Aß in the brain of mice. EK100 and antrodin C are significantly different in activating astrocytes, regulating microglia morphology, and promoting plaque-associated microglia to express oxidative enzymes. In contrast, the effects of ibuprofen and ergosterol are relatively small. In addition, EK100 significantly improved hippocampal neurogenesis in APPswe/PS1dE9 mice. Our data indicate that EK100 and antrodin C reduce the pathology of AD by reducing amyloid deposits and promoting nesting behavior in APPswe/PS1dE9 mice through microglia and perivascular clearance, indicating that EK100 and antrodin C have the potential to be used in AD treatment.

2.
Behav Neurol ; 2021: 6301458, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34336001

RESUMO

Prenatal exposure to buprenorphine renders offspring vulnerable to cerebral impairments. In this study, our data demonstrate, for the first time, that prenatal exposure to buprenorphine escalates astrocyte activation concurrent with indications of endoplasmic reticulum (ER) stress in the hippocampi of neonates, and this can be prevented by the coadministration of dextromethorphan with buprenorphine. Furthermore, dextromethorphan can inhibit the accumulation of GPR37 in the hippocampus of newborns caused by buprenorphine and is accompanied by the proapoptotic ER stress response that involves the procaspase-3/CHOP pathway. Primary astrocyte cultures derived from the neonates of the buprenorphine group also displayed aberrant ER calcium mobilization and elevated basal levels of cyclooxygenase-2 (COX-2) at 14 days in vitro while showing sensitivity to lipopolysaccharide-activated expression of COX-2. Similarly, these long-lasting defects in the hippocampus and astrocytes were abolished by dextromethorphan. Our findings suggest that prenatal exposure to buprenorphine might instigate long-lasting effects on hippocampal and astrocytic functions. The beneficial effects of prenatal coadministration of dextromethorphan might be, at least in part, attributed to its properties in attenuating astrocyte activation and hippocampal ER stress in neonates.


Assuntos
Buprenorfina , Efeitos Tardios da Exposição Pré-Natal , Apoptose , Astrócitos , Dextrometorfano/toxicidade , Estresse do Retículo Endoplasmático , Feminino , Humanos , Recém-Nascido , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente
3.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360989

RESUMO

Increasing evidence suggests that elderly people with dementia are vulnerable to the development of severe coronavirus disease 2019 (COVID-19). In Alzheimer's disease (AD), the major form of dementia, ß-amyloid (Aß) levels in the blood are increased; however, the impact of elevated Aß levels on the progression of COVID-19 remains largely unknown. Here, our findings demonstrate that Aß1-42, but not Aß1-40, bound to various viral proteins with a preferentially high affinity for the spike protein S1 subunit (S1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the viral receptor, angiotensin-converting enzyme 2 (ACE2). These bindings were mainly through the C-terminal residues of Aß1-42. Furthermore, Aß1-42 strengthened the binding of the S1 of SARS-CoV-2 to ACE2 and increased the viral entry and production of IL-6 in a SARS-CoV-2 pseudovirus infection model. Intriguingly, data from a surrogate mouse model with intravenous inoculation of Aß1-42 show that the clearance of Aß1-42 in the blood was dampened in the presence of the extracellular domain of the spike protein trimers of SARS-CoV-2, whose effects can be prevented by a novel anti-Aß antibody. In conclusion, these findings suggest that the binding of Aß1-42 to the S1 of SARS-CoV-2 and ACE2 may have a negative impact on the course and severity of SARS-CoV-2 infection. Further investigations are warranted to elucidate the underlying mechanisms and examine whether reducing the level of Aß1-42 in the blood is beneficial to the fight against COVID-19 and AD.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Fragmentos de Peptídeos/metabolismo , SARS-CoV-2/enzimologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Células A549 , Doença de Alzheimer/complicações , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/química , Animais , COVID-19/complicações , COVID-19/metabolismo , Chlorocebus aethiops , Humanos , Interleucina-6/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fragmentos de Peptídeos/química , Subunidades Proteicas/química , Subunidades Proteicas/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Células Vero , Internalização do Vírus
4.
Neurobiol Aging ; 90: 60-74, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31879131

RESUMO

High-fat and high-sugar diets contribute to the prevalence of type 2 diabetes and Alzheimer's disease (AD). Although the impact of high-fat diets on AD pathogenesis has been established, the effect of high-sucrose diets (HSDs) on AD pathogenesis remains unclear. This study sought to determine the impact of HSDs on AD-related pathologies. Male APPswe/PS1dE9 (APP/PS1) transgenic and wild-type mice were provided with HSD and their cognitive and hypothalamus-related noncognitive parameters, including feeding behaviors and glycemic regulation, were compared. HSD-fed APP/PS1 mice showed increased neuroinflammation, as well as increased cortical and serum levels of amyloid-ß. HSD-fed APP/PS1 mice showed aggravated obesity, hyperinsulinemia, insulin resistance, and leptin resistance, but there was no induction of hyperphagia or hyperleptinemia. Leptin-induced phosphorylation of signal transducer and activator of transcription 3 in the dorsomedial and ventromedial hypothalamus was reduced in HSD-fed APP/PS1 mice, which might be associated with attenuated food-anticipatory activity, glycemic dysregulation, and AD-related noncognitive symptoms. Our study demonstrates that HSD aggravates metabolic stresses, increases AD-related pathologies, and attenuates hypothalamic leptin signaling in APP/PS1 mice.


Assuntos
Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Antecipação Psicológica/efeitos dos fármacos , Dieta da Carga de Carboidratos/efeitos adversos , Ingestão de Alimentos/psicologia , Hipotálamo/metabolismo , Leptina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sacarose/efeitos adversos , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Animais , Inflamação , Camundongos Transgênicos , Fator de Transcrição STAT3/metabolismo
5.
J Neuroinflammation ; 16(1): 123, 2019 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-31176371

RESUMO

BACKGROUND: Astrocyte activation is a common pathological feature in many brain diseases with neuroinflammation, and revealing the underlying mechanisms might shed light on the regulatory processes of the diseases. Recently, soluble epoxide hydrolase (sEH) has been proposed to affect neuroinflammation in brain injuries. However, the roles of astrocytic sEH in brains with neurodegeneration remain unclear. METHODS: The expression of astrocytic sEH in the brains of APPswe/PSEN1dE9 (APP/PS1) mice developing Alzheimer's disease (AD)-like pathology was evaluated by confocal imaging. LPS-activated primary astrocytes with mRNA silencing or overexpression of sEH were used to investigate its regulatory roles in astrocyte activation and the induction of pro-inflammatory markers. Primary astrocytes isolated from a sEH knockout (sEH-/-) background were also applied. RESULTS: The immunoreactivity of sEH was increased in activated astrocytes in parallel with the progression of AD in APP/PS1 mice. Our data from primary astrocyte cultures further demonstrate that the overexpression of sEH ameliorated, while the silencing of sEH mRNA enhanced, the lipopolysaccharides (LPS)-induced expression of pro-inflammatory markers, such as inducible nitric oxide, cyclooxygenase 2 (COX-2), and pro-inflammatory cytokines. These findings suggest that sEH negatively regulates astrocyte immune responses. Enhanced immune responses found in LPS-activated sEH-/- astrocytes also support the notion that the expression of sEH could suppress the immune responses during astrocyte activation. Similarly, sEH-/- mice that received intraperitoneal injection of LPS showed exacerbated astrocyte activation in the brain, as observed by the elevated expression of glial fibrillary acidic protein (GFAP) and pro-inflammatory markers. Moreover, our data show that the phosphorylation of the signal transducer and activator of transcription 3 (STAT3) was upregulated in activated astrocytes from sEH mouse brains, and the pharmacological blockade of STAT3 activity alleviated the pro-inflammatory effects of sEH deletion in LPS-activated primary astrocytes. CONCLUSIONS: Our results provide evidence, for the first time, showing that sEH negatively regulates astrocytic immune responses and GFAP expression, while the underlying mechanism at least partly involves the downregulation of STAT3 phosphorylation. The discovery of a novel function for sEH in the negative control of astrocytic immune responses involving STAT3 activation confers further insights into the regulatory machinery of astrocyte activation during the development of neurodegeneration.


Assuntos
Astrócitos/imunologia , Epóxido Hidrolases/imunologia , Fator de Transcrição STAT3/imunologia , Doença de Alzheimer/imunologia , Doença de Alzheimer/metabolismo , Animais , Astrócitos/metabolismo , Epóxido Hidrolases/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Fator de Transcrição STAT3/metabolismo
6.
Int J Mol Sci ; 19(8)2018 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-30096853

RESUMO

Alzheimer's disease (AD), a progressive neurodegenerative disease is highly associated with metabolic syndromes. We previously demonstrated that glycemic dysregulation and obesity are augmented in high fat diet (HFD)-treated APPswe/PS1dE9 (APP/PS1) transgenic mice. In the current study, the underlying mechanism mediating exacerbated metabolic stresses in HFD APP/PS1 transgenic mice was further examined. APP/PS1 mice developed insulin resistance and, consequently, impaired glucose homeostasis after 10 weeks on HFD. [18F]-2-fluoro-2-deoxy-d-glucose ([18F]-FDG) positron emission tomography showed that interscapular brown adipose tissue is vulnerable to HFD and AD-related pathology. Chronic HFD induced hyperphagia, with limited effects on basal metabolic rates in APP/PS1 transgenic mice. Excessive food intake may be caused by impairment of leptin signaling in the hypothalamus because leptin failed to suppress the food intake of HFD APP/PS1 transgenic mice. Leptin-induced pSTAT3 signaling in the arcuate nucleus was attenuated. Dysregulated energy homeostasis including hyperphagia and exacerbated obesity was elicited prior to the presence of the amyloid pathology in the hypothalamus of HFD APP/PS1 transgenic mice; nevertheless, cortical neuroinflammation and the level of serum Aß and IL-6 were significantly elevated. Our study demonstrates the pivotal role of AD-related pathology in augmenting HFD-induced insulin and leptin resistance and impairing hypothalamic regulation of energy homeostasis.


Assuntos
Doença de Alzheimer/genética , Hiperfagia/tratamento farmacológico , Resistência à Insulina/genética , Obesidade/genética , Tecido Adiposo Marrom/efeitos dos fármacos , Doença de Alzheimer/complicações , Doença de Alzheimer/patologia , Animais , Glicemia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Ingestão de Alimentos/genética , Homeostase , Humanos , Hiperfagia/genética , Hiperfagia/patologia , Insulina/metabolismo , Insulina/uso terapêutico , Leptina/metabolismo , Leptina/uso terapêutico , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/genética , Síndrome Metabólica/patologia , Camundongos , Camundongos Transgênicos , Obesidade/complicações , Obesidade/patologia
7.
Int J Mol Sci ; 19(2)2018 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-29463001

RESUMO

Hericium erinaceus was used in traditional Chinese medicine for physiologically beneficial medicines. Recently, it has become a candidate in causing positive brain health-related activities. We previously reported that Hericium erinaceus mycelium ameliorates Alzheimer's disease (AD)-related pathologies. To reveal the role of the cyanthin diterpenoid and sesterterpene constituents on this effects, erinacine A and S were isolated and their effects on attenuating AD-related pathology in APPswe/PS1dE9 transgenic mice were investigated. A 30 day short-term administration of erinacine A and S were performed to explore the effect of each erinacine on AD-related pathology including amyloid ß production and degradation, plaque formation, plaque growth, glial activation and neurogenesis deterioration. Our results indicated the benefit effects of both erinacine A and S in cerebrum of APPswe/PS1dE9 mice, including: (1) attenuating cerebral plaque loading by inhibiting plaque growth; (2) diminishing the activation of glial cells; (3) raising the level of insulin degrading enzyme; and (4) promoting hippocampal neurogenesis. Moreover, erinacine A reduced the level of insoluble amyloid ß and C-terminal fragment of amyloid precursor protein which was not mediated by erinacine S. We further performed a long term administration of erinacine A and found that erinacine A recovered the impairment in the tasks including burrowing, nesting, and Morris water maze. Our data pointed out that although both erinacine A and S reduce AD pathology via reducing amyloid deposition and promoting neurogenesis, erinacine A can also inhibit amyloid ß production and is worth to be further developed for AD therapeutic use.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Neurogênese/efeitos dos fármacos , Placa Amiloide/tratamento farmacológico , Agregação Patológica de Proteínas/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/genética , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/genética , Animais , Basidiomycota/química , Diterpenos/administração & dosagem , Diterpenos/química , Hipocampo/efeitos dos fármacos , Hipocampo/crescimento & desenvolvimento , Humanos , Insulisina/genética , Camundongos , Camundongos Transgênicos , Micélio/química , Neuroglia/efeitos dos fármacos , Oligopeptídeos/genética , Placa Amiloide/genética , Placa Amiloide/patologia , Agregação Patológica de Proteínas/genética , Agregação Patológica de Proteínas/patologia , Sesterterpenos/administração & dosagem , Sesterterpenos/química
8.
Int J Mol Sci ; 18(12)2017 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-29258283

RESUMO

Astragalus membranaceus is commonly used in traditional Chinese medicine for strengthening the host defense system. Astragalus membranaceus-polysaccharides is an effective component with various important bioactivities, such as immunomodulation, antioxidant, anti-diabetes, anti-inflammation and neuroprotection. In the present study, we determine the effects of Astragalus membranaceus-polysaccharides on metabolically stressed transgenic mice in order to develop this macromolecules for treatment of sporadic Alzheimer's disease, a neurodegenerative disease with metabolic risk factors. Transgenic mice, at 10 weeks old prior to the appearance of senile plaques, were treated in combination of administrating high-fat diet and injecting low-dose streptozotocin to create the metabolically stressed mice model. Astragalus membranaceus-polysaccharides was administrated starting at 14 weeks for 7 weeks. We found that Astragalus membranaceus-polysaccharides reduced metabolic stress-induced increase of body weight, insulin and insulin and leptin level, insulin resistance, and hepatic triglyceride. Astragalus membranaceus-polysaccharides also ameliorated metabolic stress-exacerbated oral glucose intolerance, although the fasting blood glucose was only temporally reduced. In brain, metabolic stress-elicited astrogliosis and microglia activation in the vicinity of plaques was also diminished by Astragalus membranaceus-polysaccharides administration. The plaque deposition, however, was not significantly affected by Astragalus membranaceus-polysaccharides administration. These findings suggest that Astragalus membranaceus-polysaccharides may be used to ameliorate metabolic stress-induced diabesity and the subsequent neuroinflammation, which improved the behavior performance in metabolically stressed transgenic mice.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Astragalus propinquus/química , Disfunção Cognitiva/tratamento farmacológico , Fígado Gorduroso/tratamento farmacológico , Obesidade/tratamento farmacológico , Polissacarídeos/uso terapêutico , Doença de Alzheimer/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Fígado Gorduroso/metabolismo , Feminino , Masculino , Camundongos , Obesidade/metabolismo
9.
J Ethnopharmacol ; 209: 50-61, 2017 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-28743670

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Metabolic syndrome and vascular dysfunction was suggested to be the risk factors for Alzheimer's disease (AD). Xuefu Zhuyu decoction (XZD) is a traditional Chinese medicine used to treat metabolic syndrome and cardiac-cerebral vascular disease. The effects of XZD on ameliorating metabolic syndrome, amyloid-related pathologies and cognitive impairment in an animal model of AD with metabolic stress was investigated. MATERIALS AND METHOD: The animal model of AD with metabolic stress was created by administrating high-fat diet and a low-dose injection of streptozotocin prior to the appearance of senile plaques in APP/PS1 transgenic mice. The diabesity-associated metabolic changes and AD-related pathological alterations were examined. RESULTS: We found that XZD reduced body weight, insulin and leptin level, HOMA-IR, hepatic triglyceride, serum Aß42 in the metabolic stressed AD animal. XZD also ameliorated oral glucose tolerant, Aß deposition, astrocyte and microglia activation in the vicinity of plaques, and nesting behavior in the metabolic stressed AD animal. CONCLUSION: The results of this study suggest that XZD is able to reduce the peripheral metabolic stress-mediated vascular hypoperfusion, neuroinflammation and AD-related pathology in APP/PS1 mice.


Assuntos
Amiloide/metabolismo , Disfunção Cognitiva/prevenção & controle , Medicamentos de Ervas Chinesas/farmacologia , Fígado Gorduroso/tratamento farmacológico , Inflamação/tratamento farmacológico , Obesidade/tratamento farmacológico , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Glicemia/efeitos dos fármacos , Homeostase , Insulina/sangue , Resistência à Insulina , Leptina/sangue , Masculino , Camundongos , Camundongos Transgênicos , Estresse Fisiológico , Triglicerídeos/metabolismo
10.
Artigo em Inglês | MEDLINE | ID: mdl-28018473

RESUMO

Background. Radix Paeoniae Rubra (Chi Shao) contains several phytochemicals with hypoglycemic actions. Current research aims to explore potential insulinotropic effects and long-term therapeutic efficacy of such herb against type 2 diabetes. Methods. Composition analysis for the ethanol extract (PRExt) was executed by high performance liquid chromatography. Polyphenol-enriched fraction was characterized by high pressure size exclusion chromatography. Multiple cell platforms were employed to evaluate hypoglycemic bioactivities. In animal experiments, blood glucose, the homeostasis model assessment (HOMA)-index assessment, glucose tolerance test, and in vivo glucose uptake were all measured. Additional effects of PRExt on obesity and hepatic steatosis were evaluated by serum and histological analysis. Results. PRExt provides multiple hypoglycemic effects including the enhancement of glucose-mediated insulin secretion. Pentagalloylglucose and polyphenol-enriched fraction are two insulinotropic constituents. Moreover, PRExt intraperitoneal injection causes acute hypoglycemic effects on fasted db/db mice. Oral administration of PRExt (200 mg/kg b.w.) gradually reduces blood glucose in db/db mice to the level similar to that in C57J/B6 mice after 30 days. The improvement of glucose intolerance, HOMA-index, and in vivo glucose uptake is evident in addition to the weight loss effect and attenuation of hepatic steatosis. Conclusion. PRExt is an effective antidiabetic herbal extract with multiple hypoglycemic bioactivities.

11.
BMC Complement Altern Med ; 16(1): 432, 2016 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-27809830

RESUMO

BACKGROUND: In this study, we aimed to develop a Stigmata Maydis (corn silk) fraction with dual bio-activities against oxidative stress and protein glycation to protect ß-cells from diabetes-induced failure. METHODS: Corn silk fractions were prepared by partition and chemically characterised by thin-layer chromatography. Free radical scavenging assay, glycation assay, and cell-based viability test (neutral red) were employed to decide the best fraction. Cell death analysis was executed by annexin V/ Propidium iodide staining. Cell proliferation was measured by WST-1. Finally, ß-cell function was evaluated by ß-cell marker gene expression (RT-PCR) and acute insulin secretion test. RESULTS: Four corn silk fractions were prepared from an ethanolic crude extract of corn silk. In vitro assays indicate ethyl acetate fraction (YMS-EA) was the most potent fraction. YMS-EA also attenuated the hydrogen peroxide- or methylglyoxal-induced induction of reactive oxygen species, reduction of cell viability, and inhibition of cell proliferation. However, YMS-EA was unable to prevent hydrogen peroxide-induced apoptosis or advanced glycation end-products-induced toxicity. Under hyperglycemic conditions, YMS-EA effectively reduced ROS levels, improved mRNA expression of insulin, glucokinase, and PDX-1, and enhanced glucose-stimulated insulin secretion. The similarity of bioactivities among apigenin, luteolin, and YMS-EA indicated that dual activities of YMS-EA might be derived from those compounds. CONCLUSIONS: We concluded that YMS-EA fraction could be developed as a preventive food agent against the glucotoxicity to ß-cells in Type 2 diabetes.


Assuntos
Antioxidantes/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Zea mays/química , Acetatos/química , Animais , Antioxidantes/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Feminino , Produtos Finais de Glicação Avançada/análise , Produtos Finais de Glicação Avançada/metabolismo , Peróxido de Hidrogênio/toxicidade , Masculino , Camundongos , Extratos Vegetais/química , Ratos , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo
12.
J Neuroinflammation ; 13(1): 92, 2016 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-27121378

RESUMO

BACKGROUND: Transient receptor potential ankyrin 1 (TRPA1) channel plays an important role in pain and inflammation. However, little is known about the significance of the TRPA1 channel in the pathophysiology of Alzheimer's disease (AD). METHODS: Wild-type (WT), TRPA1(-/-), amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic (APP/PS1 Tg) mice, the mouse model of AD, and APP/PS1 Tg/TRPA1(-/-) mice were used to examine the role of TRPA1 in pathogenesis of AD. Western blot was used for protein expression; immunohistochemistry was used for histological examination. The mouse behaviors were evaluated by locomotion, nesting building, Y-maze and Morris water maze tests; levels of interleukin (IL)-1ß, IL-4, IL-6 and IL-10 and the activities of protein phosphatase 2B (PP2B), NF-κB and nuclear factor of activated T cells (NFAT) were measured by conventional assay kits; Fluo-8 NW calcium (Ca(2+)) assay kit was used for the measurement of intracellular Ca(2+) level in primary astrocytes and HEK293 cells. RESULTS: The protein expression of TRPA1 channels was higher in brains, mainly astrocytes of the hippocampus, from APP/PS1 Tg mice than WT mice. Ablation of TRPA1-channel function in APP/PS1 Tg mice alleviated behavioral dysfunction, Aß plaque deposition and pro-inflammatory cytokine production but increased astrogliosis in brain lesions. TRPA1 channels were activated and Ca(2+) influx was elicited in both astrocytes and TRPA1-transfected HEK293 cells treated with fibrilized Aß1-42; these were abrogated by pharmacological inhibition of TRPA1 channel activity, disruption of TRPA1 channel function or removal of extracellular Ca(2+). Inhibition of TRPA1 channel activity exacerbated Aß1-42-induced astrogliosis but inhibited Aß1-42-increased PP2B activation, the production of pro-inflammatory cytokines and activities of transcriptional factors NF-κB and NFAT in astrocytes and in APP/PS1 Tg mice. Pharmacological inhibition of PP2B activity diminished the fibrilized Aß1-42-induced production of pro-inflammatory cytokines, activation of NF-κB and NFAT and astrogliosis in astrocytes. CONCLUSIONS: TRPA1 - Ca(2+) - PP2B signaling may play a crucial role in regulating astrocyte-derived inflammation and pathogenesis of AD.


Assuntos
Doença de Alzheimer/metabolismo , Astrócitos/metabolismo , Canais de Potencial de Receptor Transitório/metabolismo , Animais , Comportamento Animal , Western Blotting , Encéfalo/metabolismo , Modelos Animais de Doenças , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transdução de Sinais/fisiologia , Canal de Cátion TRPA1
13.
J Biomed Sci ; 23: 27, 2016 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-26892079

RESUMO

BACKGROUND: The accumulation of soluble oligomeric amyloid-ß peptide (oAß) proceeding the formation of senile plaques contributes to synaptic and memory deficits in Alzheimer's disease. Our previous studies have indentified scavenger receptor A (SR-A), especially SR-A type I (SR-AI), as prominent scavenger receptors on mediating oAß clearance by microglia while glycan moiety and scavenger receptor cysteine-rich (SRCR) domain may play the critical role. Macrophage receptor with collagenous structure (MARCO), another member of class A superfamily with a highly conserved SRCR domain, may also play the similar role on oAß internalization. However, the role of N-glycosylation and SRCR domain of SR-AI and MARCO on oAß internalization remains unclear. RESULT: We found that oAß internalization was diminished in the cells expressing SR-AI harboring mutations of dual N-glycosylation sites (i.e. N120Q-N143Q and N143Q-N184Q) while they were normally surface targeted. Normal oAß internalization was observed in 10 SR-AI-SRCR and 4 MARCO-SRCR surface targeted mutants. Alternatively, the SRCR mutants at ß-sheet and α-helix and on disulfide bone formation obstructed receptor's N-glycosylation and surface targeting. CONCLUSION: Our study reveals that N-glycan moiety is more critical than SRCR domain for SR-A-mediated oAß internalization.


Assuntos
Proteínas de Transporte/metabolismo , Receptores Imunológicos/metabolismo , Substituição de Aminoácidos , Peptídeos beta-Amiloides , Animais , Células COS , Proteínas de Transporte/genética , Chlorocebus aethiops , Glicosilação , Células HEK293 , Humanos , Mutação de Sentido Incorreto , Estrutura Terciária de Proteína , Transporte Proteico/genética , Receptores Imunológicos/genética , Fatores de Processamento de Serina-Arginina
14.
PLoS One ; 10(8): e0134531, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26244977

RESUMO

Diabesity-associated metabolic stresses modulate the development of Alzheimer's disease (AD). For further insights into the underlying mechanisms, we examine whether the genetic background of APPswe/PS1dE9 at the prodromal stage of AD affects peripheral metabolism in the context of diabesity. We characterized APPswe/PS1dE9 transgenic mice treated with a combination of high-fat diet with streptozotocin (HFSTZ) in the early stage of AD. HFSTZ-treated APPswe/PS1dE9 transgenic mice exhibited worse metabolic stresses related to diabesity, while serum ß-amyloid levels were elevated and hepatic steatosis became apparent. Importantly, two-way analysis of variance shows a significant interaction between HFSTZ and genetic background of AD, indicating that APPswe/PS1dE9 transgenic mice are more vulnerable to HFSTZ treatment. In addition, body weight gain, high hepatic triglyceride, and hyperglycemia were positively associated with serum ß-amyloid, as validated by Pearson's correlation analysis. Our data suggests that the interplay between genetic background of AD and HFSTZ-induced metabolic stresses contributes to the development of obesity and hepatic steatosis. Alleviating metabolic stresses including dysglycemia, obesity, and hepatic steatosis could be critical to prevent peripheral ß-amyloid accumulation at the early stage of AD.


Assuntos
Peptídeos beta-Amiloides/sangue , Diabetes Mellitus Experimental/sangue , Fígado Gorduroso/sangue , Obesidade/sangue , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Análise de Variância , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Modelos Animais de Doenças , Ácidos Graxos não Esterificados/sangue , Humanos , Leptina/sangue , Lipídeos/sangue , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fragmentos de Peptídeos/sangue , Presenilina-1/genética , Presenilina-1/metabolismo , Estresse Fisiológico/genética , Triglicerídeos/metabolismo , Ganho de Peso
15.
Neurobiol Aging ; 36(11): 2984-2994, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26264859

RESUMO

Although metabolic syndrome was suggested to be a risk factor for Alzheimer's disease (AD), the role of metabolic stress in the initiation of AD pathology remains unclear. In this study, metabolic stress was induced by a high-fat diet and low-dose injection of streptozotocin (HFSTZ) before the appearance of senile plaques in APP/PS1 transgenic mice. We found that, HFSTZ treatment exacerbated amyloid beta burden and astrocyte activation in the vicinity of plaques. Moreover, we observed an upregulation of astrocytic S100B expression in the brain parenchyma of HFSTZ-treated APP/PS1 mice concurrent with increased interleukin-6 expression in cerebral microvascular cells. To determine the impact of HFSTZ treatment on brain function, we performed [(18)F]fludeoxyglucose-positron emission tomography and analyzed nesting behavior. HFSTZ treatment impaired nest construction and cerebral glucose metabolism in several brain regions of APP/PS1 mice during the early stage of AD. These results suggest that HFSTZ-induced peripheral metabolic stress may contribute to vascular inflammation and astrocyte reactivity in the parenchyma and may impair activity of daily living skill and cerebral glucose metabolism in APP/PS1 mice.


Assuntos
Astrócitos/metabolismo , Astrócitos/patologia , Encéfalo/metabolismo , Transtornos Cognitivos/etiologia , Glucose/metabolismo , Estresse Fisiológico/fisiologia , Doença de Alzheimer/etiologia , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/irrigação sanguínea , Proteína Glial Fibrilar Ácida/metabolismo , Interleucina-6/metabolismo , Masculino , Síndrome Metabólica/etiologia , Camundongos Transgênicos , Microvasos/metabolismo , Obesidade/etiologia , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Estreptozocina
16.
J Biomed Sci ; 22: 37, 2015 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-26018660

RESUMO

BACKGROUND: Parkinson's disease is the second most common neurodegenerative disorders after Alzheimer's disease. The main cause of the disease is the massive degeneration of dopaminergic neurons in the substantia nigra. Neuronal apoptosis and neuroinflammation are thought to be the key contributors to the neuronal degeneration. RESULTS: Both CATH.a cells and ICR mice were treated with 1-methyl-4-phenylpyridin (MPP(+)) to induce neurotoxicity in vitro and in vivo. Western blotting and immunohistochemistry were also used to analyse neurotoxicity, neuroinflammation and aberrant neurogenesis in vivo. The experiment in CATH.a cells showed that the treatment of MPP(+) impaired intake of cell membrane and activated caspase system, suggesting that the neurotoxic mechanisms of MPP(+) might include both necrosis and apoptosis. Pretreatment of lithospermic acid might prevent these toxicities. Lithospermic acid possesses specific inhibitory effect on caspase 3. In mitochondria, MPP(+) caused mitochondrial depolarization and induced endoplasmic reticulum stress via increasing expression of chaperone protein, GRP-78. All the effects mentioned above were reduced by lithospermic acid. In animal model, the immunohistochemistry of mice brain sections revealed that MPP(+) decreased the amount of dopaminergic neurons, enhanced microglia activation, promoted astrogliosis in both substantia nigra and hippocampus, and MPP(+) provoked the aberrant neurogenesis in hippocampus. Lithospermic acid significantly attenuates all of these effects induced by MPP(+). CONCLUSIONS: Lithospermic acid is a potential candidate drug for the novel therapeutic intervention on Parkinson's disease.


Assuntos
Anti-Inflamatórios/farmacologia , Benzofuranos/farmacologia , Depsídeos/farmacologia , Neurônios/efeitos dos fármacos , 1-Metil-4-fenilpiridínio/toxicidade , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Inflamação/imunologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Neurogênese/efeitos dos fármacos , Neurônios/imunologia
17.
J Biomed Sci ; 20: 90, 2013 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-24313976

RESUMO

BACKGROUND: The roles of caspase 3 on the kainic acid-mediated neurodegeneration, dendritic plasticity alteration, neurogenesis, microglial activation and gliosis are not fully understood. Here, we investigate hippocampal changes using a mouse model that receive a single kainic acid-intracerebral ventricle injection. The effects of caspase 3 inhibition on these changes were detected during a period of 1 to 7 days post kainic acid injection. RESULT: Neurodegeneration was assessed by Fluoro-Jade B staining and neuronal nuclei protein (NeuN) immunostaining. Neurogenesis, gliosis, neuritic plasticity alteration and caspase 3 activation were examined using immunohistochemistry. Dendritic plasticity, cleavvage-dependent activation of calcineurin A and glial fibrillary acidic protein cleavage were analyzed by immunoblotting. We found that kainic acid not only induced neurodegeneration but also arouse several caspase 3-mediated molecular and cellular changes including dendritic plasticity, neurogenesis, and gliosis. The acute caspase 3 activation occurred in pyramidal neurons as well as in hilar interneurons. The delayed caspase 3 activation occurred in astrocytes. The co-injection of caspase 3 inhibitor did not rescue kainic acid-mediated neurodegeneration but seriously and reversibly disturb the structural integrity of axon and dendrite. The kainic acid-induced events include microglia activation, the proliferation of radial glial cells, neurogenesis, and calcineurin A cleavage were significantly inhibited by the co-injection of caspase 3 inhibitor, suggesting the direct involvement of caspase 3 in these events. Alternatively, the kainic acid-mediated astrogliosis is not caspase 3-dependent, although caspase 3 cleavage of glial fibrillary acidic protein occurred. CONCLUSIONS: Our results provide the first direct evidence of a causal role of caspase 3 activation in the cellular changes during kainic acid-mediated excitotoxicity. These findings may highlight novel pharmacological strategies to arrest disease progression and control seizures that are refractory to classical anticonvulsant treatment.


Assuntos
Caspase 3/genética , Epilepsia/fisiopatologia , Hipocampo/efeitos dos fármacos , Ácido Caínico/toxicidade , Neurogênese/efeitos dos fármacos , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Caspase 3/metabolismo , Epilepsia/induzido quimicamente , Hipocampo/metabolismo , Imuno-Histoquímica , Infusões Intraventriculares , Masculino , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Plasticidade Neuronal/efeitos dos fármacos
18.
Schizophr Res ; 151(1-3): 1-11, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24113206

RESUMO

Maternal infection and maternal immune activation (MIA) during pregnancy increase risks for psychiatric disorders such as schizophrenia and autism. Many deficits related to psychiatric disorders are observed in adult offspring of MIA animal models, including behavioral abnormalities, morphological defects in various brain regions, and dysregulation of neurotransmitter systems. It has previously been shown that MIA impairs adult neurogenesis in the dentate gyrus of the hippocampus. In this study, we examined whether MIA affects adult neurogenesis in the subventricular zone (SVZ)-olfactory bulb (OB) pathway. Polyinosinic-polycytidylic acid (PolyI:C), a synthetic analog of double-stranded RNA mimicking viral infection, was injected into pregnant mice on gestation day 9.5 to activate immune systems. In the SVZ-OB pathway of adult offspring, different cell types of the neural stem cell lineage responded differently to MIA. Neural stem cells and neuroblasts were decreased. Cell proliferation of transit-amplifying cells was impaired. Consequently, newborn neurons were reduced in the OB. Olfactory deficiency has been suggested as a biomarker for schizophrenia. Here we found that olfactory discrimination was compromised in adult MIA offspring. Taken together, these findings show that MIA leads to defective adult neurogenesis in the SVZ-OB pathway, and the impairment of adult neurogenesis may lead to deficits in olfactory functions.


Assuntos
Ventrículos Cerebrais/patologia , Discriminação Psicológica/fisiologia , Neurogênese/fisiologia , Bulbo Olfatório/patologia , Condutos Olfatórios/patologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Olfato/fisiologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proliferação de Células/efeitos dos fármacos , Discriminação Psicológica/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/patologia , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Neurogênese/efeitos dos fármacos , Neuropeptídeos/metabolismo , Bulbo Olfatório/efeitos dos fármacos , Condutos Olfatórios/efeitos dos fármacos , Poli I-C/toxicidade , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Fatores de Transcrição SOXB1/metabolismo , Olfato/efeitos dos fármacos , Olfato/imunologia
19.
J Biomed Sci ; 20: 78, 2013 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-24152138

RESUMO

BACKGROUND: The specific role of microglia on Aß-mediated neurotoxicity is difficult to assign in vivo due to their complicated environment in the brain. Therefore, most of the current microglia-related studies employed the isolated microglia. However, the previous in vitro studies have suggested either beneficial or destructive function in microglia. Therefore, to investigate the phenotypes of the isolated microglia which exert activity of neuroprotective or destructive is required. RESULTS: The present study investigates the phenotypes of isolated microglia on protecting neuron against Aß-mediated neurotoxicity. Primary microglia were isolated from the mixed glia culture, and were further cultured to distinct phenotypes, designated as proliferating amoeboid microglia (PAM) and differentiated process-bearing microglia (DPM). Their inflammatory phenotypes, response to amyloid ß (Aß), and the beneficial or destructive effects on neurons were investigated. DPM may induce both direct neurotoxicity without exogenous stimulation and indirect neurotoxicity after Aß activation. On the other hand, PAM attenuates Aß-mediated neurotoxicity through Aß phagocytosis and/or Aß degradation. CONCLUSIONS: Our results suggest that the proliferating microglia, but not the differentiated microglia, protect neurons against Aß-mediated neurotoxicity. This discovery may be helpful on the therapeutic investigation of Alzheimer's disease.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/toxicidade , Córtex Cerebral/metabolismo , Microglia/metabolismo , Neurônios/metabolismo , Animais , Proliferação de Células , Células Cultivadas , Córtex Cerebral/citologia , Camundongos , Microglia/citologia , Neurônios/citologia , Fenótipo , Ratos , Ratos Sprague-Dawley
20.
J Biomed Sci ; 20: 54, 2013 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-23915271

RESUMO

BACKGROUND: Insufficient clearance of soluble oligomeric amyloid-ß peptide (oAß) in the central nervous system leads to the synaptic and memory deficits in Alzheimer's disease (AD). Previously we have identified scavenger receptor class A (SR-A) of microglia mediates oligomeric amyloid-ß peptide (oAß) internalization by siRNA approach. SR-A is a member of cysteine-rich domain (SRCR) superfamily which contains proteins actively modulating the innate immunity and host defense, however the functions of the SRCR domain remain unclear. Whether the SRCR domain of SR-AI modulates the receptor surface targeting and ligand internalization was investigated by expressing truncated SR-A variants in COS-7 cells. Surface targeting of SR-A variants was examined by live immunostaining and surface biotinylation assays. Transfected COS-7 cells were incubated with fluorescent oAß and acetylated LDL (AcLDL) to assess their ligand-internalization capabilities. RESULT: Genetic ablation of SR-A attenuated the internalization of oAß and AcLDL by microglia. Half of oAß-containing endocytic vesicles was SR-A positive in both microglia and macrophages. Clathrin and dynamin in SR-AI-mediated oAß internalization were involved. The SRCR domain of SR-AI is encoded by exons 10 and 11. SR-A variants with truncated exon 11 were intracellularly retained, whereas SR-A variants with further truncations into exon 10 were surface-targeted. The fusion of exon 11 to the surface-targeted SR-A variant lacking the SRCR domain resulted in the intracellular retention and the co-immunoprecipitation of Bip chaperon of the endoplasmic reticulum. Surface-targeted variants were N-glycosylated, whereas intracellularly-retained variants retained in high-mannose states. In addition to the collagenous domain, the SRCR domain is a functional binding domain for oAß and AcLDL. Our data suggest that inefficient folding of SR-AI variants with truncated SRCR domain was recognized by the endoplasmic reticulum associated degradation which leads to the immature N- glycosylation and intracellular retention. CONCLUSION: The novel functions of the SRCR domain on regulating the efficacy of receptor trafficking and ligand binding may lead to possible approaches on modulating the innate immunity in Alzheimer's disease and atherosclerosis.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Estrutura Terciária de Proteína , Receptores Depuradores Classe A/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/genética , Animais , Células COS , Chlorocebus aethiops , Cisteína/genética , Citoplasma/metabolismo , Retículo Endoplasmático/química , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Humanos , Lipoproteínas LDL/genética , Lipoproteínas LDL/metabolismo , Dobramento de Proteína , Proteólise , Receptores Depuradores Classe A/química , Receptores Depuradores Classe A/genética , Propriedades de Superfície
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