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1.
Neurobiol Aging ; 101: 94-108, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33610062

RESUMO

Despite effective clearance of parenchymal amyloid-ß (Aß) in patients with Alzheimer's disease, Aß immunotherapy exacerbates the vascular Aß (VAß)-associated pathology in the brain. We have previously shown that BCG immunization facilitates protective monocyte recruitment to the brain of APP/PS1 mice. Here, we confirmed that the 4Aß1-15 vaccine exacerbates VAß deposits in this model, which coincides with a decrease in the number of cerebrovascular endothelial cells and pericytes, infiltration of neutrophils into the brain, and induction of cerebral microhemorrhage. Moreover, combined 4Aß1-15/BCG treatment abrogates the development of the VAß-associated pathology. In addition, BCG treatment is required for the upregulation of interleukin-10 in the brain. Notably, BCG treatment selectively enhances Aß phagocytosis by recruited macrophages. Furthermore, combined 4Aß1-15/BCG treatment is more effective than 4Aß1-15 monotherapy in synaptic preservation and the enhancement of the learning efficiency. Overall, our study suggests that the combination of Aß-targeted therapy with an immunomodulatory strategy may improve the efficacy of Aß vaccine in Alzheimer's disease.


Assuntos
Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/metabolismo , Vacina BCG/administração & dosagem , Encéfalo/metabolismo , Imunoterapia Ativa/métodos , Doença de Alzheimer/imunologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Animais , Vacina BCG/farmacologia , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Interleucina-10/metabolismo , Aprendizagem , Macrófagos/imunologia , Macrófagos/patologia , Camundongos Transgênicos , Fagocitose/efeitos dos fármacos
2.
Brain Behav Immun ; 91: 128-141, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32956831

RESUMO

Immune dysfunction is implicated in Alzheimer's disease (AD), whereas systemic immune modulation may be neuroprotective. Our previous results have indicated immune challenge with Bacillus Calmette-Guerin attenuates AD pathology in animal models by boosting the systemic immune system. Similarly, independent studies have shown that boosting systemic immune system, by blocking PD-1 checkpoint pathway, modifies AD. Here we hypothesized that influenza vaccine would potentiate function of moderate dose anti-PD-1 and therefore combining them might allow reducing the dose of PD-1 antibody needed to modify the disease. We found that moderate-dose PD-1 in combination with influenza vaccine effectively attenuated cognitive deficit and prevented amyloid-ß pathology build-up in APP/PS1 mice in a mechanism dependent on recruitment of peripheral monocyte-derived macrophages into the brain. Eliminating peripheral macrophages abrogated the beneficial effect. Moreover, by comparing CD11b+ compartments in the mouse parenchyma, we observed an elevated subset of Ly6C+ microglia-like cells, which are reportedly derived from peripheral monocytes. In addition, myeloid-derived suppressor cells are strongly elevated in the transgenic model used and normalized by combination treatment, indicating restoration of brain immune homeostasis. Overall, our results suggest that revitalizing brain immunity by combining IV with moderate-dose PD-1 inhibition may represent a therapeutic immunotherapy for AD.


Assuntos
Doença de Alzheimer , Vacinas contra Influenza , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/metabolismo , Cognição , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Presenilina-1
3.
Age Ageing ; 50(1): 190-197, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-32556149

RESUMO

BACKGROUND: multimorbidity contributes to a large portion of the disease burden in low- and middle-income countries. However, limited research has been undertaken in China. This study has investigated the prevalence of multimorbidity and the associations of multimorbidity with activities of daily living (ADL), instrumental activities of daily living (IADL) and depression in China. METHODS: the study participants included 10,055 adults aged 45 years and older from three rounds of the China Health and Retirement Longitudinal Study 2011-2015. Random-effects logistic regression models were used to examine the association of multimorbidity with ADL limitation, IADL limitation and mental disease. RESULTS: the prevalence of multimorbidity amongst adults in China aged 45 years and older was 62.1% in 2015. The prevalence of multimorbidity was increased with older age, among women, in a higher socio-economic group and in the most deprived regions. Multimorbidity is associated with an increased likelihood of experiencing ADL limitation (adjusted odds ratio [AOR] = 5.738, 95% confidence intervals (CI) = 5.733, 5.744) and IADL limitation (AOR = 2.590, 95% CI = 2.588, 2.592) and depression (AOR = 3.352, 95% CI = 3.350, 3.354). Rural-urban disparities in functional difficulties and depression were also found amongst patients with multimorbidity. CONCLUSIONS: the burden of multimorbidity is high in China, particularly amongst the older population. Multimorbidity is associated with higher levels of functional limitations and depression. China healthcare reforms should introduce integrated care models and patient-centred healthcare delivery. The increasing need for reorientation of healthcare resources considering the distribution of multimorbidity and its adverse effect requires more attention from health policymakers in China and other developing countries.


Assuntos
Atividades Cotidianas , Multimorbidade , Idoso , China/epidemiologia , Estudos Transversais , Depressão/diagnóstico , Depressão/epidemiologia , Feminino , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade
4.
Nature ; 588(7836): 61-65, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33268866

RESUMO

The standard model of particle physics is remarkably successful because it is consistent with (almost) all experimental results. However, it fails to explain dark matter, dark energy and the imbalance between matter and antimatter in the Universe. Because discrepancies between standard-model predictions and experimental observations may provide evidence of new physics, an accurate evaluation of these predictions requires highly precise values of the fundamental physical constants. Among them, the fine-structure constant α is of particular importance because it sets the strength of the electromagnetic interaction between light and charged elementary particles, such as the electron and the muon. Here we use matter-wave interferometry to measure the recoil velocity of a rubidium atom that absorbs a photon, and determine the fine-structure constant α-1 = 137.035999206(11) with a relative accuracy of 81 parts per trillion. The accuracy of eleven digits in α leads to an electron g factor1,2-the most precise prediction of the standard model-that has a greatly reduced uncertainty. Our value of the fine-structure constant differs by more than 5 standard deviations from the best available result from caesium recoil measurements3. Our result modifies the constraints on possible candidate dark-matter particles proposed to explain the anomalous decays of excited states of 8Be nuclei4 and paves the way for testing the discrepancy observed in the magnetic moment anomaly of the muon5 in the electron sector6.

5.
Cell Death Dis ; 11(6): 440, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32514180

RESUMO

Autophagy is a major self-degradative process that maintains cellular homeostasis and function in mammalian cells. Autophagic dysfunction occurs in the early pathogenesis of Alzheimer's disease (AD) and directly regulates amyloid-ß (Aß) metabolism. Although it has been proven that the cytokine IFN-γ enhances autophagy in macrophage cell lines, whether the signaling cascade is implicated in Aß degradation in AD mouse models remains to be elucidated. Here, we found that 9 days of the intraperitoneal administration of IFN-γ significantly increased the LC3II/I ratio and decreased the level of p62 in APP/PS1 mice, an AD mouse model. In vitro, IFN-γ protected BV2 cells from Aß toxicity by upregulating the expressions of Atg7 and Atg5 and the LC3II/I ratio, whereas these protective effects were ablated by interference with Atg5 expression. Moreover, IFN-γ enhanced autophagic flux, probably through suppressing the AKT/mTOR pathway both in vivo and in vitro. Importantly, using intravital two-photon microscopy and fluorescence staining, we found that microglia interacted with exogenous IFN-γ and Aß, and surrounded Aß in APP/PS1;CX3CR1-GFP+/- mice. In addition, IFN-γ treatment decreased the Aß plaque load in the cortex and hippocampus and rescued cognitive deficits in APP/PS1 mice. Our data suggest a possible mechanism by which the peripheral injection of IFN-γ restores microglial autophagy to induce the phagocytosis of cerebral Aß, which represents a potential therapeutic approach for the use of exogenous IFN-γ in AD.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Cognição/efeitos dos fármacos , Injeções Intraperitoneais/métodos , Interferon-alfa/uso terapêutico , Microglia/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Masculino , Camundongos
6.
PLoS One ; 15(4): e0225874, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32240169

RESUMO

We previously have reported that neonatal Bacillus Calmette-Guerin (BCG) vaccination improves neurogenesis and behavior in early life through affecting the neuroimmune milieu in the brain, but it is uncertain whether activation phenotypes and functional changes in T lymphocytes shape brain development. Here, we studied the effects of BCG vaccination via the adoptive transfer of T lymphocytes from the BALB/c wild-type mice into naive mice. Our results show that mice adoptive BCG-induced lymphocytes (BCG->naive mice) showed anxiolytic and antidepressant-like performance when completing an elevated plus maze (EPM) test. Meanwhile, BCG->naive mice possess more cell proliferation and newborn neurons than PBS->naive and nude mice in the hippocampus. IFN-γ and IL-4 levels in the serum of BCG->naive mice also increased, while TNF-α and IL-1ß levels were reduced relative to those of PBS->naive and nude mice. We further found that BCG->naive mice showed different repartition of CD4+ and CD8+ T cell to naive (CD62L+CD44low), effector memory (CD62L-CD44hi), central memory (CD62L+CD44hi) and acute/activated effector (CD62L-CD44low) cells in the spleen. Importantly, the adoptive transfer of BCG-induced T lymphocytes infiltrated into the dura mater and brain parenchyma of the nude mice. Activation phenotypes and functional changes in T lymphocytes are very likely to affect the neuroimmune milieu in the brain, and alterations in ratios of splenic CD4+ and CD8+ memory T cells may affect the expression of correlative cytokines in the serum, accounting for our behavioral results. We conclude thus that the adoptive transfer of BCG-induced T lymphocytes contributes to hippocampal cell proliferation and tempers anxiety-like behavior in immune deficient mice. Our work shows that BCG vaccination improves hippocampal cell proliferation outcomes and behaviors, likely as a result of splenic effector/memory T lymphocytes regulating the neuroimmune niche in the brain.


Assuntos
Ansiedade/tratamento farmacológico , Vacina BCG/farmacologia , Proliferação de Células/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Ansiedade/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Receptores de Hialuronatos/genética , Interferon gama/genética , Interleucina-4/genética , Selectina L/genética , Linfócitos/efeitos dos fármacos , Linfócitos/patologia , Camundongos , Camundongos Nus
7.
J Neuroinflammation ; 17(1): 65, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32075657

RESUMO

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder strongly correlated with a dysfunctional immune system. Our previous results demonstrated that inactivated influenza vaccine (IIV) facilitates hippocampal neurogenesis and blocks lipopolysaccharide (LPS)-induced cognitive impairment. However, whether IIV improves cognitive deficits in an AD mouse model remains unclear. In addition, early interventions in AD have been encouraged in recent years. Here, we investigated whether IIV immunization at the preclinical stage of AD alters the brain pathology and cognitive deficits in an APP/ PS1 mouse model. METHODS: We assessed spatial learning and memory using Morris water maze (MWM). The brain ß-amyloid (Aß) plaque burden and activated microglia were investigated by immunohistochemistry. Furthermore, flow cytometry was utilized to analyze the proportions of Treg cells in the spleen. A cytokine antibody array was performed to measure the alteration of cytokines in the brain and peripheral immune system. RESULTS: Five IIV immunizations activated microglia, reduced the Aß burden and improved the cognitive impairment. Simultaneously, the IIV-induced immune response broke peripheral immunosuppression by reducing Foxp3+ regulatory T cell (Treg) activities, whereas the restoration of Treg level in the periphery using all-trans retinoic acid (ATRA) blunted the protective effects of IIV on Aß burden and cognitive functions. Interestingly, IIV immunization might increase proinflammatory and anti-inflammatory cytokine expression in the brain of APP/PS1 mice, enhanced microglial activation, and enhanced the clustering and phagocytosis of Aß, thereby creating new homeostasis in the disordered immune microenvironment. CONCLUSIONS: Altogether, our results suggest that early multiple IIV immunizations exert a beneficial immunomodulatory effect in APP/PS1 mice by breaking Treg-mediated systemic immune tolerance, maintaining the activation of microglia and removing of Aß plaques, eventually improving cognitive deficits.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Precursor de Proteína beta-Amiloide , Amiloidose/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Vacinas contra Influenza/administração & dosagem , Presenilina-1 , Linfócitos T Reguladores/efeitos dos fármacos , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Amiloidose/genética , Amiloidose/patologia , Animais , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Presenilina-1/genética , Linfócitos T Reguladores/patologia
8.
Brain Res Bull ; 149: 268-278, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31051226

RESUMO

Previous study has demonstrated the neurobeneficial role of BCG and influenza vaccines. Based on this, our study concentrated on the synergistic effects on development of central nervous system by combined vaccination with BCG and influenza vaccines in rats. Our results displayed that pups combinedly vaccinated with BCG and influenza vaccines showed a significant enhance in spatial cognition, induction of LTP, hippocampal neurogenesis and morphology of dendritic spines compared with pups vaccinated with BCG solely. Furthermore, combined vaccination with BCG and influenza vaccines showed higher expression of BDNF, IGF-1, IL-4, IFN-γ and lower IL-1ß, TNF-α and IL-6 than BCG. Taken together, combined vaccination with BCG and influenza vaccines presented synergistic effects on spatial cognition and hippocampal plasticity in rats.


Assuntos
Vacina BCG/metabolismo , Cognição/efeitos dos fármacos , Vacinas contra Influenza/metabolismo , Animais , Animais Recém-Nascidos , Vacina BCG/farmacologia , Encéfalo/metabolismo , Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Sinergismo Farmacológico , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Vacinas contra Influenza/farmacologia , Masculino , Aprendizagem em Labirinto/fisiologia , Neurogênese/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Navegação Espacial/efeitos dos fármacos , Lobo Temporal/metabolismo , Vacinação
9.
Autism Res ; 12(4): 576-588, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30681777

RESUMO

Maternal immune activation (MIA) is associated with an increased risk for autism spectrum disorders (ASD) in offspring. Animal experiments have found that interleukin 6 (IL-6) and IL-17a are key cytokines in the induction of ASD by MIA. Moreover, probiotics were verified to inhibit the production of proinflammatory cytokines. Therefore, we investigated whether the administration of oral probiotics during pregnancy might protect the offspring that have suffered MIA from developing ASD. Probiotics were orally administered to pregnant mice with/without the simultaneous administration of Poly(I:C). We found that oral probiotics prevented the ASD-like behaviors induced by MIA in offspring. Furthermore, oral probiotics prevented the MIA-induced increases in the IL-6 and IL-17a levels in both maternal serum and fetal brains, parvalbumin positive (PV+ ) neuron loss, and the decrease in the γ-aminobutyric acid levels in the prefrontal cortex of adult offspring. This work suggests that administering oral probiotics during pregnancy may help decrease the risk of ASD following MIA during pregnancy. Autism Res 2019, 12: 576-588. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Interleukin 6 (IL-6) and IL-17a are key cytokines in the maternal immune activation (MIA)-induced autism spectrum disorders (ASD). Based on emerging evidence that probiotics can inhibit the production of proinflammatory cytokines, we found that oral probiotics prevented MIA-induced ASD-like behaviors in offspring. This work suggested that oral probiotics during pregnancy may be an effective means for decreasing the incidence of ASD in offspring.


Assuntos
Transtorno do Espectro Autista/prevenção & controle , Comportamento Animal , Inflamação/prevenção & controle , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Probióticos/farmacologia , Administração Oral , Animais , Modelos Animais de Doenças , Feminino , Inflamação/imunologia , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/imunologia , Probióticos/administração & dosagem
10.
J Neuroinflammation ; 15(1): 228, 2018 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-30103815

RESUMO

BACKGROUND: Prenatal infection is a substantial risk factor for neurodevelopmental disorders such as autism in offspring. We have previously reported that influenza vaccination (VAC) during early pregnancy contributes to neurogenesis and behavioral function in offspring. RESULTS: Here, we probe the efficacy of VAC pretreatment on autism-like behaviors in a lipopolysaccharide (LPS)-induced maternal immune activation (MIA) mouse model. We show that VAC improves abnormal fetal brain cytoarchitecture and lamination, an effect associated with promotion of intermediate progenitor cell differentiation in MIA fetal brain. These beneficial effects are sufficient to prevent social deficits in adult MIA offspring. Furthermore, whole-genome analysis suggests a strong interaction between Ikzf1 (IKAROS family zinc-finger 1) and neuronal differentiation. Intriguingly, VAC rescues excessive microglial Ikzf1 expression and attenuates microglial inflammatory responses in the MIA fetal brain. CONCLUSIONS: Our study implies that a preprocessed influenza vaccination prevents maternal bacterial infection from causing neocortical lamination impairments and autism-related behaviors in offspring.


Assuntos
Transtorno Autístico/complicações , Vacinas contra Influenza/uso terapêutico , Malformações do Desenvolvimento Cortical/prevenção & controle , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Transtornos do Comportamento Social/prevenção & controle , Animais , Animais Recém-Nascidos , Receptor 1 de Quimiocina CX3C/genética , Receptor 1 de Quimiocina CX3C/metabolismo , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Lipopolissacarídeos/toxicidade , Masculino , Malformações do Desenvolvimento Cortical/etiologia , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Transtornos do Comportamento Social/etiologia , Natação/fisiologia , Natação/psicologia
11.
Neural Regen Res ; 13(4): 709-716, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29722325

RESUMO

Impaired amyloid-ß clearance from the brain is a core pathological event in Alzheimer's disease. The therapeutic effect of current pharmacotherapies is unsatisfactory, and some treatments cause severe side effects. The meningeal lymphatic vessels might be a new route for amyloid-ß clearance. This study investigated whether promoting dural lymphangiogenesis facilitated the clearance of amyloid-ß from the brain. First, human lymphatic endothelial cells were treated with 100 ng/mL recombinant human vascular endothelial growth factor-C (rhVEGF-C) protein. Light microscopy verified that rhVEGF-C, a specific ligand for vascular endothelial growth factor receptor-3 (VEGFR-3), significantly promoted tube formation of human lymphatic endothelial cells in vitro. In an in vivo study, 200 µg/mL rhVEGF-C was injected into the cisterna magna of APP/PS1 transgenic mice, once every 2 days, four times in total. Immunofluorescence staining demonstrated high levels of dural lymphangiogenesis in Alzheimer's disease mice. One week after rhVEGF-C administration, enzyme-linked immunosorbent assay results showed that levels of soluble amyloid-ß were decreased in cerebrospinal fluid and brain. The Morris water maze test demonstrated that spatial cognition was restored. These results indicate that the upregulation of dural lymphangiogenesis facilities amyloid-ß clearance from the brain of APP/PS1 mice, suggesting the potential of the VEGF-C/VEGFR-3 signaling pathway as a therapeutic target for Alzheimer's disease.

12.
Cytokine ; 110: 137-149, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29751176

RESUMO

We have previously verified that neonatal hepatitis B vaccination induced hippocampal neuroinflammation and behavior impairments in mice. However, the exact mechanism of these effects remain unclear. In this study, we observed that neonatal hepatitis B vaccination induced an anti-inflammatory cytokine response lasting for 4-5 weeks in both the serum and the hippocampus, primarily indicated by elevated IL-4 levels. Three weeks after the vaccination schedule, however, hepatitis B vaccine (HBV)-mice showed delayed hippocampal neuroinflammation. In periphery, IL-4 is the major cytokine induced by this vaccine. Correlation analyses showed a positive relationship in the IL-4 levels between serum and hippocampus in HBV-mice. Thus, we investigated whether neonatal over-exposure to systemic IL-4 influences brain and behavior. We observed that mice injected intraperitoneally with recombinant mouse IL-4 (mIL-4) during early life had similar neuroinflammation and cognition impairment similar to those induced by neonatal hepatitis B vaccination. Next, the mechanism underlying the effects of IL-4 on brain in mice was explored using a series of experiments. In brief, these experiments showed that IL-4 mediates the delayed neurobehavioral impairments induced by neonatal hepatitis B vaccination, which involves the permeability of neonatal blood-brain barrier and the down-regulation of IL-4 receptor. This finding suggests that clinical events concerning neonatal IL-4 over-exposure, including neonatal hepatitis B vaccination and allergic asthma in human infants, may have adverse implications for brain development and cognition.


Assuntos
Regulação para Baixo/efeitos dos fármacos , Vacinas contra Hepatite B/efeitos adversos , Hipocampo/efeitos dos fármacos , Doenças do Sistema Nervoso/induzido quimicamente , Receptores de Interleucina-4/metabolismo , Vacinação/efeitos adversos , Animais , Animais Recém-Nascidos , Barreira Hematoencefálica/efeitos dos fármacos , Citocinas/metabolismo , Hepatite B/imunologia , Vacinas contra Hepatite B/imunologia , Vírus da Hepatite B/imunologia , Hipocampo/metabolismo , Humanos , Lactente , Interleucina-4/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Doenças do Sistema Nervoso/metabolismo
13.
Brain Behav Immun ; 71: 116-132, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29627530

RESUMO

Activation of the neonatal immune system may contribute to deficits in neuronal plasticity. We have reported that neonatal vaccination with a hepatitis B vaccine (HBV) transiently impairs mood status and spatial memory involving a systemic T helper (Th) 2 bias and M1 microglial activation. Here, an EE induced microglial anti-inflammatory M2 polarization, as evidenced by selectively enhanced expression of the Arginase1 gene (Arg-1) in the hippocampus. Interestingly, knock-down of the Arg-1 gene prevented the effects of EE on restoring the dendritic spine density. Moreover, levels of the Th1-derived cytokine IFN-gamma (IFN-γ) were elevated in the choroid plexus (CP), which is the interface between the brain and the periphery. IFN-γ-blocking antibodies blunted the protective effects of an EE on spine density and LTP. Furthermore, levels of complement proteins C1q and C3 were elevated, and this elevation was associated with synapse loss induced by the HBV, whereas an EE reversed the effects of the HBV. Similarly, blockade of C1q activation clearly prevented synaptic pruning by microglia, LTP inhibition and memory deficits in hepatitis B-vaccinated mice. Together, the EE-induced increase in IFN-γ levels in the CP may disrupt systemic immunosuppression related to HBV via an IFN-γ/Arg-1/complement-dependent pathway.


Assuntos
Vacinas contra Hepatite B/efeitos adversos , Plasticidade Neuronal/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Arginase/efeitos dos fármacos , Arginase/genética , Citocinas , Meio Ambiente , Feminino , Hepatite B , Hipocampo/efeitos dos fármacos , Interferon gama/efeitos dos fármacos , Interferon gama/genética , Masculino , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/imunologia , Transtornos da Memória/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/imunologia , Neurogênese/imunologia , Plasticidade Neuronal/fisiologia , Células Th2/efeitos dos fármacos , Vacinação/efeitos adversos
14.
Sensors (Basel) ; 17(12)2017 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-29189728

RESUMO

Four-transistor (T) pinned photodiode (PPD) CMOS image sensors (CISs) with four-megapixel resolution using 11µm pitch high dynamic range pixel were radiated with 3 MeV and 10MeV protons. The dark signal was measured pre- and post-radiation, with the dark signal post irradiation showing a remarkable increase. A theoretical method of dark signal distribution pre- and post-radiation is used to analyze the degradation mechanisms of the dark signal distribution. The theoretical results are in good agreement with experimental results. This research would provide a good understanding of the proton radiation effects on the CIS and make it possible to predict the dark signal distribution of the CIS under the complex proton radiation environments.

15.
J Neuroinflammation ; 14(1): 32, 2017 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-28183352

RESUMO

BACKGROUND: The spatial learning abilities of developing mice benefit from extrinsic cues, such as an enriched environment, with concomitant enhancement in cognitive functions. Interestingly, such enhancements can be further increased through intrinsic Bacillus Calmette-Guérin (BCG) vaccination. RESULTS: Here, we first report that combined neonatal BCG vaccination and exposure to an enriched environment (Enr) induced combined neurobeneficial effects, including hippocampal long-term potentiation, and increased neurogenesis and spatial learning and memory, in mice exposed to the Enr and vaccinated with BCG relative to those in the Enr that did not receive BCG vaccination. Neonatal BCG vaccination markedly induced anti-inflammatory meningeal macrophage polarization both in regular and Enr breeding mice. The meninges are composed of the pia mater, dura mater, and choroid plexus. Alternatively, this anti-inflammatory activity of the meninges occurred simultaneously with increased expression of the neurotrophic factors BDNF/IGF-1 and the M2 microglial phenotype in the hippocampus. Our results reveal a critical role for BCG vaccination in the regulation of neurogenesis and spatial cognition through meningeal macrophage M2 polarization and neurotrophic factor expression; these effects were completely or partially prevented by minocycline or anti-IL-10 antibody treatment, respectively. CONCLUSIONS: Together, we first claim that immunological factor and environmental factor induce a combined effect on neurogenesis and cognition via a common pathway-meningeal macrophage M2 polarization. We also present a novel functional association between peripheral T lymphocytes and meningeal macrophages after evoking adaptive immune responses in the periphery whereby T lymphocytes are recruited to the meninges in response to systemic IFN-γ signaling. This leads to meningeal macrophage M2 polarization, subsequent to microglial M2 activation and neurotrophic factor expression, and eventually promotes a positive behavior.


Assuntos
Vacina BCG/administração & dosagem , Cognição/fisiologia , Meio Ambiente , Macrófagos/metabolismo , Neurogênese/fisiologia , Comportamento Espacial/fisiologia , Animais , Animais Recém-Nascidos , Polaridade Celular/efeitos dos fármacos , Polaridade Celular/fisiologia , Cognição/efeitos dos fármacos , Feminino , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Meninges/efeitos dos fármacos , Meninges/imunologia , Meninges/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/efeitos dos fármacos , Comportamento Espacial/efeitos dos fármacos
16.
Neurotox Res ; 31(2): 204-217, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27848175

RESUMO

Severe hand-foot-and-mouth disease (HFMD) caused by Enterovirus 71 (EV71) always accompanies with inflammation and neuronal damage in the central nervous system (CNS). During neuronal injuries, cell surface-exposed calreticulin (Ecto-CRT) is an important mediator for primary phagocytosis of viable neurons by microglia. Our data confirmed that brainstem neurons underwent neuronophagia by glia in EV71-induced death cases of HFMD. EV71 capsid proteins VP1, VP2, VP3, or VP4 did not induce apoptosis of brainstem neurons. Interestingly, we found VP1-activated endoplasmic reticulum (ER) stress and autophagy could promote Ecto-CRT upregulation, but ER stress or autophagy alone was not sufficient to induce CRT exposure. Furthermore, we demonstrated that VP1-induced autophagy activation was mediated by ER stress. Meaningfully, we found dexamethasone treatment could attenuate Ecto-CRT upregulation by alleviating VP1-induced ER stress. Altogether, these findings identify VP1-promoted Ecto-CRT upregulation as a novel mechanism of EV71-induced neuronal cell damage and highlight the potential of the use of glucocorticoids to treat severe HFMD patients with CNS complications.


Assuntos
Calreticulina/metabolismo , Proteínas do Capsídeo/toxicidade , Dexametasona/farmacologia , Estresse do Retículo Endoplasmático/fisiologia , Neurônios/fisiologia , Fagocitose/fisiologia , Proteínas Estruturais Virais/toxicidade , Animais , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Tronco Encefálico/efeitos dos fármacos , Tronco Encefálico/fisiopatologia , Células Cultivadas , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Humanos , Masculino , Fagocitose/efeitos dos fármacos , Ratos , Regulação para Cima
17.
Psychoneuroendocrinology ; 73: 166-176, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27501128

RESUMO

The immune system plays a vital role in brain development. The hepatitis B vaccine (HBV) is administered to more than 70% of neonates worldwide. Whether this neonatal vaccination affects brain development is unknown. Newborn C57BL/6 mice were injected intraperitoneally with HBV or phosphate-buffered saline. HBV induced impaired behavioral performances and hippocampal long-term potentiation at 8 weeks (w) of age without influence at 4 or 12w. At 6w, there was decreased neurogenesis, M1 microglial activation and a neurotoxic profile of neuroimmune molecule expression [increased tumor necrosis factor-α and reduced interferon (IFN)-γ, brain-derived neurotrophic factor and insulin-like growth factor-1] in the hippocampus of the HBV-vaccinated mice. In the serum, HBV induced significantly higher levels of interleukin (IL)-4, indicating a T helper (Th)-2 bias. Moreover, the serum IFN-γ/IL-4 ratio was positively correlated with the levels of neurotrophins and neurogenesis in the hippocampus at the individual level. These findings suggest that neonatal HBV vaccination of mice results in neurobehavioral impairments in early adulthood by inducing a proinflammatory and low neurotrophic milieu in the hippocampus, which follows the HBV-induced systemic Th2 bias.


Assuntos
Comportamento Animal , Citocinas/sangue , Vacinas contra Hepatite B/efeitos adversos , Hipocampo/imunologia , Microglia/imunologia , Neurogênese/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL
18.
Mol Med Rep ; 14(2): 1574-86, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27357155

RESUMO

The Bacillus Calmette-Guérin (BCG) vaccine is routinely administered to human neonates worldwide. BCG has recently been identified as a neuroprotective immune mediator in several neuropathological conditions, exerting neuroprotection in a mouse model of Parkinson's disease and slowing the progression of clinically isolated syndrome in patients with multiple sclerosis. The immune system is significantly involved in brain development, and several types of neonatal immune activations exert influences on the brain and behavior following a secondary immune challenge in adulthood. However, whether the neonatal BCG vaccination affects the brain in adulthood remains to be elucidated. In the present study, newborn C57BL/6 mice were injected subcutaneously with BCG (105 colony forming units) or phosphate­buffered saline (PBS). A total of 12 weeks later, the mice were injected intraperitoneally with 330 µg/kg lipopolysaccharide (LPS) or PBS. The present study reported that the neonatal BCG vaccination alleviated sickness, anxiety and depression­like behavior, lessened the impairments in hippocampal cell proliferation and downregulated the proinflammatory responses in the serum and brain that were induced by the adult LPS challenge. However, BCG vaccination alone had no evident influence on the brain and behavior in adulthood. In conclusion, the neonatal BCG vaccination alleviated the neurobehavioral impairments and neuroinflammation induced by LPS exposure in adult mice, suggesting a potential neuroprotective role of the neonatal BCG vaccination in adulthood.


Assuntos
Vacina BCG/imunologia , Comportamento Animal , Imunização , Inflamação/fisiopatologia , Doenças do Sistema Nervoso/fisiopatologia , Fármacos Neuroprotetores/imunologia , Fatores Etários , Animais , Animais Recém-Nascidos , Ansiedade , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Citocinas/metabolismo , Depressão , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Inflamação/etiologia , Inflamação/terapia , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/efeitos adversos , Camundongos , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/terapia , Polissacarídeos/metabolismo , Serotonina/metabolismo
19.
Hum Vaccin Immunother ; 12(1): 140-9, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26375414

RESUMO

Dendritic structure is sensitive to changes in the environment during brain development. Accumulating evidence has demonstrated that early immune activation can significantly affect neuronal development. Our study concentrated on the morphological study of neural dendrites and spines in the hippocampal CA1 area using Diolistic labeling with Sholl analysis and fractal analysis. The results revealed that Bacille Calmette-Guérin (BCG) vaccination enhanced dendritic complexity, as reflected by the increased number of intersections, number of branch points and fractal dimension, and promoted neurite outgrowth. In addition, BCG increased the density and promoted the maturation of dendritic spines. The alterations in dendritic structure and spine morphology were observed at 2 and 4 w, but the differences were more apparent at 4 w than at 2 w. However, no significant difference was observed at 8 w. Furthermore, we observed that BCG increased the expression of hippocampal brain derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF-1). Hippocampal BDNF/IGF-1 was positively correlated with apical dendritic length, fractal dimension, and spine density. Taken together, we show in this study that neonatal BCG vaccination promotes dendritic development in developing hippocampal CA1 neurons, most likely by increasing the expression of BDNF and IGF-1 in the hippocampus.


Assuntos
Vacina BCG/administração & dosagem , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/crescimento & desenvolvimento , Dendritos/fisiologia , Neurônios/fisiologia , Animais , Animais Recém-Nascidos , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Expressão Gênica , Fator de Crescimento Insulin-Like I/biossíntese , Ratos Sprague-Dawley
20.
Brain Res Bull ; 120: 25-33, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26536170

RESUMO

Bacillus Calmette-Guérin (BCG) is administered to neonates worldwide, but it is still unknown whether this neonatal vaccination affects brain development during early postnatal life, despite the close association of the immune system with the brain. Newborn C57BL/6 mice were injected subcutaneously with BCG or phosphate-buffered saline (PBS) and their mood status and spatial cognition were observed at four and eight weeks (w) old. The mice were also subjected to tests at 2 and 6 w to examine BCG's effects on neurogenesis, the hippocampal microglia phenotype and number, and the expression of hippocampal neuroimmune molecules and peripheral cytokines. The BCG-injected mice showed better behavioral performances at 4 w. We observed elevated neurogenesis, M2 microglial activation and a neurotrophic profile of neuroimmune molecules [more interferon (IFN)-γ, interleukin (IL)-4, transforming growth factor (TGF)-ß, brain-derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF)-1 and less tumor necrosis factor (TNF)-α and IL-1ß] in the hippocampus of the 2-w-old BCG-mice. In the periphery, BCG induced a T helper (Th)-1 serum response. At the individual level, there were positive correlations between the serum IFN-γ/IL-4 ratio and the levels of neurotrophins and neurogenesis in the hippocampus. These findings suggest that neonatal BCG vaccination improved neurogenesis and mouse behavior in early life by affecting the neuroimmune milieu in the brain, which may be associated with a systemic Th1 bias.


Assuntos
Vacina BCG , Hipocampo/imunologia , Microglia/imunologia , Neurogênese/imunologia , Animais , Animais Recém-Nascidos , Transtornos de Ansiedade/imunologia , Transtornos de Ansiedade/prevenção & controle , Fatores de Transcrição Hélice-Alça-Hélice Básicos/sangue , Feminino , Hipocampo/citologia , Interferon gama/sangue , Interleucina-4 , Masculino , Aprendizagem em Labirinto , Microglia/citologia , Atividade Motora/imunologia , Memória Espacial
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