RESUMO
Activation of innate immunity in the brain is a prominent feature of Alzheimer's disease (AD). The present study investigated the regulation of innate immunity by wild-type serum injection in a transgenic AD mouse model. We found that treatment with wild-type mouse serum significantly reduced the number of neutrophils and microglial reactivity in the brains of APP/PS1 mice. Mimicking this effect, neutrophil depletion via Ly6G neutralizing antibodies resulted in improvements in AD brain functions. Serum proteomic analysis identified vascular endothelial growth factor-A (VEGF-A) and chemokine (C-X-C motif) ligand 1 (CXCL1) as factors enriched in serum samples, which are crucial for neutrophil migration and chemotaxis, leukocyte migration, and cell chemotaxis. Exogenous VEGF-A reversed amyloid ß (Aß)-induced decreases in cyclin-dependent kinase 5 (Cdk5) and increases in CXCL1 in vitro and blocked neutrophil infiltration into the AD brain. Endothelial Cdk5 overexpression conferred an inhibitory effect on CXCL1 and neutrophil infiltration, thereby restoring memory abilities in APP/PS1 mice. Our findings uncover a previously unknown link between blood-derived VEGF signaling and neutrophil infiltration and support targeting endothelial Cdk5 signaling as a potential therapeutic strategy for AD.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Camundongos , Animais , Camundongos Transgênicos , Fator A de Crescimento do Endotélio Vascular , Infiltração de Neutrófilos , Proteômica , Doença de Alzheimer/terapia , Transtornos da Memória , Modelos Animais de Doenças , Precursor de Proteína beta-Amiloide/genética , Presenilina-1/genéticaRESUMO
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-1RESUMO
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/patologiaRESUMO
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/psicologiaRESUMO
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 4-5â¯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/metabolismoRESUMO
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 adversosRESUMO
The immune system plays a crucial role in the progression of Alzheimer's disease (AD). Recently, immune-dependent cascade induced by systemic immune activation has been verified to play a beneficial role in AD mouse models. Here, we tested whether Bacillus Calmette-Guérin (BCG) immunization alters AD pathology and cognitive dysfunction in APP/PS1 AD mouse model, and with 4Aß1-15 vaccination as positive control. It was found that BCG treatment reversed the cognitive decline to the extent observed in 4Aß1-15 group, but did not reduce the ß-amyloid (Aß) burden in the brain. Then, we demonstrated the enhanced recruitment of inflammation-resolving monocytes across the choroid plexus and perivascular spaces to cerebral sites of plaque pathology in APP/PS1 mice immunized with BCG. Furthermore, elevated splenocyte Foxp3+ regulatory T cell levels in the control APP/PS1 mice were down-regulated back to the wild-type (WT) levels by BCG treatment but not 4Aß1-15 vaccination. In addition, BCG treatment induced the production of more circulating interferon (IFN)-γ than the controls and 4Aß1-15 vaccination. Though the similar reductions in brain levels of pro-inflammatory cytokines were observed in the BCG and 4Aß1-15 groups compared to the controls, only BCG had the great effect in upregulating cerebral anti-inflammatory cytokine levels as well as elevating the expression of neurotrophic factors in the brain of APP/PS1 mice. Thus, it is suggested that BCG exerts a beneficial immunomodulatory effect in APP/PS1 mice through mitigation of systemic immune suppression, induction of IFN-γ response and alleviation of the neuroinflammatory response.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/imunologia , Vacina BCG/uso terapêutico , Encéfalo/imunologia , Monócitos/imunologia , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/imunologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Fatores de Transcrição Forkhead/metabolismo , Gliose/tratamento farmacológico , Gliose/imunologia , Gliose/patologia , Humanos , Interleucina-10/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Monócitos/efeitos dos fármacos , Monócitos/patologia , Fragmentos de Peptídeos/imunologia , Baço/citologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologiaRESUMO
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 fármacosRESUMO
BACKGROUND AND OBJECTIVES: Chronic colitis exacerbates neuroinflammation, contributing to cognitive impairment during aging, but the mechanism remains unclear. The polarity distribution of astrocytic aquaporin 4 (AQP4) is crucial for the glymphatic system, which is responsible for metabolite clearance in the brain. Physical exercise (PE) improves cognition in the aged. This study aims to investigate the protective mechanism of exercise in colitis-associated cognitive impairment. METHODS: To establish a chronic colitis model, 18-month-old C57BL/6 J female mice received periodic oral administration of 1% wt/vol dextran sodium sulfate (DSS) in drinking water. The mice in the exercise group received four weeks of voluntary wheel exercise. High-throughput sequencing was conducted to screen for differentially expressed genes. Two-photon imaging was performed to investigate the function of the astrocytic calcium activity and in vivo intervention with TRPV4 inhibitor HC-067047. Further, GSK1016790A (GSK1), a TRPV4 agonist, was daily intraperitoneally injected during the exercise period to study the involvement of TRPV4 in PE protection. Colitis pathology was confirmed by histopathology. The novel object recognition (NOR) test, Morris water maze test (MWM), and open field test were performed to measure colitis-induced cognition and anxiety-like behavior. In vivo two-photon imaging and ex vivo imaging of fluorescent CSF tracers to evaluate the function of the glymphatic system. Immunofluorescence staining was used to detect the Aß deposition, polarity distribution of astrocytic AQP4, and astrocytic phenotype. Serum and brain levels of the inflammatory cytokines were tested by Enzyme-linked immunosorbent assay (ELISA). The brain TUNEL assay was used to assess DNA damage. Expression of critical molecules was detected using Western blotting. RESULTS: Voluntary exercise alleviates cognitive impairment and anxiety-like behavior in aged mice with chronic colitis, providing neuroprotection against neuronal damage and apoptosis. Additionally, voluntary exercise promotes the brain clearance of Aß via increased glymphatic clearance. Mechanistically, exercise-induced beneficial effects may be attributed, in part, to the inhibition of TRPV4 expression and TRPV4-related calcium hyperactivity, subsequent promotion of AQP4 polarization, and modulation of astrocyte phenotype. CONCLUSION: The present study reveals a novel role of voluntary exercise in alleviating colitis-related cognitive impairment and anxiety disorder, which is mediated by the promotion of AQP4 polarization and glymphatic clearance of Aß via inhibition of TRPV4-induced astrocytic calcium hyperactivity.
Assuntos
Astrócitos , Disfunção Cognitiva , Colite , Sistema Glinfático , Condicionamento Físico Animal , Canais de Cátion TRPV , Animais , Feminino , Camundongos , Envelhecimento , Aquaporina 4/metabolismo , Astrócitos/metabolismo , Cálcio/metabolismo , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Colite/induzido quimicamente , Colite/complicações , Colite/metabolismo , Sistema Glinfático/metabolismo , Camundongos Endogâmicos C57BL , Morfolinas , Condicionamento Físico Animal/fisiologia , Pirróis , Canais de Cátion TRPV/metabolismoRESUMO
The effectiveness of coronavirus disease 2019 (COVID-19) vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain rapidly wanes over time. Growing evidence from epidemiological studies suggests that influenza vaccination is associated with a reduction in the risk of SARS-CoV-2 infection and COVID-19 severity. However, the underlying mechanisms remain elusive. Here, we investigate the cross-reactive immune responses of influenza vaccination to SARS-CoV-2 spike protein peptides based on in vitro study. Our data indicate enhanced activation-induced-marker (AIM) expression on CD4+ T cells in influenza-vaccination (IV)-treated peripheral blood mononuclear cells (PBMCs) upon stimulation with spike-protein-peptide pools. The fractions of other immune cell subtypes, including CD8+ T cells, monocytes, NK cells, and antigen-presenting cells, were not changed between IV-treated and control PBMCs following ex vivo spike-protein-peptide stimulation. However, the classical antiviral (IFN-γ) and anti-inflammatory (IL-1RA) cytokine responses to spike-protein-peptide stimulation were still enhanced in PBMCs from both IV-immunized adult and aged mice. Decreased expression of proinflammatory IL-1ß, IL-12p40, and TNF-α is associated with inhibited levels of histone acetylation in PBMCs from IV-treated mice. Remarkably, prior immunity to SARS-CoV-2 does not result in modification of histone acetylation or hemagglutinin-protein-induced cytokine responses. This response is antibody-independent but can be mediated by manipulating the histone acetylation of PBMCs. These data experimentally support that influenza vaccination could induce modification of histone acetylation in immune cells and reveal the existence of potential cross-reactive immunity to SARS-CoV-2 antigens, which may provide insights for the adjuvant of influenza vaccine to limit COVID-19-related inflammatory responses.
RESUMO
Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder leading to cognitive decline. Excessive cytosolic calcium (Ca2+) accumulation plays a critical role in the pathogenesis of AD since it activates the NOD-like receptor family, pyrin domain containing 3 (NLRP3), switches the endoplasmic reticulum (ER) unfolded protein response (UPR) toward proapoptotic signaling and promotes Aß seeding. Herein, a liposomal nanodrug (felodipine@LND) is developed incorporating a calcium channel antagonist felodipine for Alzheimer's disease treatment through a low-intensity pulse ultrasound (LIPUS) irradiation-assisted blood brain barrier (BBB)-crossing drug delivery. The multifunctional felodipine@LND is effectively delivered to diseased brain through applying a LIPUS irradiation to the skull, which resulted in a series of positive effects against AD. Markedly, the nanodrug treatment switched the ER UPR toward antioxidant signaling, prevented the surface translocation of ER calreticulin (CALR) in microglia, and inhibited the NLRP3 activation and Aß seeding. In addition, it promoted the degradation of damaged mitochondria via mitophagy, thereby inhibiting the neuronal apoptosis. Therefore, the anxiety-like behavior and cognitive impairment of 5xFAD mice with AD is significantly ameliorated, which manifested the potential of LIPUS - assisted BBB-crossing delivery of felodipine@LND to serve as a paradigm for AD therapy based on the well-recognized clinically available felodipine.
RESUMO
BACKGROUND: Neuroinflammation and oxidative stress are important pathological mechanisms underlying cerebral ischemic stroke. Increasing evidence suggests that regulation autophagy in ischemic stroke may improve neurological functions. In this study, we aimed to explore whether exercise pretreatment attenuates neuroinflammation and oxidative stress in ischemic stroke by improving autophagic flux. METHODS: 2,3,5-Triphenyltetrazolium chloride staining was used to determine the infarction volume, and modified Neurological Severity Scores and rotarod test were used to evaluate neurological functions after ischemic stroke. The levels of oxidative stress, neuroinflammation, neuronal apoptosis and degradation, autophagic flux, and signaling pathway proteins were determined using immunofluorescence, dihydroethidium, TUNEL, and Fluoro-Jade B staining, western blotting, and co-immunoprecipitation. RESULTS: Our results showed that, in middle cerebral artery occlusion (MCAO) mice, exercise pretreatment improved neurological functions and defective autophagy, and reduced neuroinflammation and oxidative stress. Mechanistically, after using chloroquine, impaired autophagy abolished the neuroprotection of exercise pretreatment. And transcription factor EB (TFEB) activation mediated by exercise pretreatment contributes to improving autophagic flux after MCAO. Furthermore, we showed that TFEB activation mediated by exercise pretreatment in MCAO was regulated by the AMPK-mTOR and AMPK-FOXO3a-SKP2-CARM1 signaling pathways. CONCLUSIONS: Exercise pretreatment has the potential to improve the prognosis of ischemic stroke patients, and it can exert neuroprotective effects in ischemic stroke by inhibiting neuroinflammation and oxidative stress, which might be due to the TFEB-mediated autophagic flux. And targeting autophagic flux may be promising strategies for the treatment of ischemic stroke.
Assuntos
AVC Isquêmico , Acidente Vascular Cerebral , Camundongos , Animais , Doenças Neuroinflamatórias , Proteínas Quinases Ativadas por AMP , Autofagia/fisiologia , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/patologia , Estresse OxidativoRESUMO
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 fármacosRESUMO
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 , CamundongosRESUMO
The common pathological hallmark of Alzheimer's disease (AD) is ß-amyloid plaques deposition. Immunotherapy is a revolutionary pharmacological treatment for AD, aiming at improving plaque clearance while concomitantly decreasing inflammation. Our previous study prepared antigen 4Aß1-15 and found that it could alleviate pathologic alterations in APP/PS1 transgenic mice. The objective of our study was to research the changing processes induced by immunotherapy, including the inflammatory factor levels and microglial activation that is closely associated with Aß burdens clearance. APP/PS1 mice were injected with 4Aß1-15 6 times. Each time, the inflammatory factors in sera were detected, and a specific fluctuation that first increased and then decreased was found, in which there was a turning point after the third injection. It prompted us to further detect the indicators in the brains after the third injection and the sixth injection. The results showed that the therapeutic effects for Aß burdens and behaviors were continuously improved during the whole immune processes, whereas the inflammatory factor levels and microglial activation experienced similar specific fluctuations. The novel discovery may provide convenient methods for further detection and evaluation of immunotherapy in disease courses.