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1.
J Neuroinflammation ; 16(1): 269, 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31847862

RESUMO

BACKGROUND: Niemann-Pick disease type C (NPC) is a progressive neurodegenerative condition that results in early fatality. NPC is inherited in an autosomal recessive pattern from mutations in NPC1 or NPC2 genes. The etiology of NPC is poorly defined. In that regard, neuroinflammation occurs early in the disease and we have recently unveiled an atypical pattern of interferon signaling in pre-symptomatic Npc1-/- mice, with microglial activation, anti-viral response, activation of antigen-presenting cells, and activation and chemotaxis of T lymphocytes as the key affected pathologic pathways. Furthermore, IP-10/CXCL10, a potent IFN-γ-responsive cytokine, was identified as the potential mediator of these early inflammatory abnormalities. Here, we asked whether this aberrant signaling may be exacerbated by the loss of amyloid precursor protein (APP) function, a loss known to shorten lifespan and accelerate neurodegeneration in Npc1-/- mice. METHODS: We carried out genome-wide comparative transcriptome analyses of pre-symptomatic Npc1+/+/App+/+, Npc1-/-/App+/+, Npc1+/+/App-/-, and Npc1-/-/App-/- mouse cerebella to identify biological pathways in the NPC brain further affected by the loss of APP. Gene Set Enrichment Analysis and Ingenuity Pathway Analysis were utilized for molecular mapping and functional upstream pathway analyses of highly differentially expressed genes. We simultaneously measured the expression of 32 inflammatory cytokines and chemokines in the cerebella from these mice, including those identified in our genome-wide analyses. Finally, we used immunohistochemistry to measure T cell infiltration in the cerebellum. RESULTS: Expression of IFN-γ- and IFN-α-responsive genes in pre-symptomatic Npc1-/-/App-/- cerebella is upregulated compared with Npc1-/-/App+/+ mice, compounding the dysregulation of microglial activation, anti-viral response, activation of antigen-presenting cells, and T-lymphocyte activation and chemotaxis pathways present in the NPC brain. Multiplex protein analysis further showed elevated expression of IP-10/CXCL10, a potent downstream effector of IFN-γ, as well as RANTES/CCL5, eotaxin/CCL11 and IL-10, prior to symptomatic onset in Npc1-/-/App-/- cerebella, compared with Npc1-/-/App+/+mice. In the terminal disease stage, loss of APP caused pleiotropic differential expression of the vast majority of cytokines evaluated. Finally, we present evidence of T cell infiltration in Npc1-/-/App-/- cerebella. CONCLUSIONS: Loss of APP exacerbates the pathogenic neuroinflammation that occurs prior to symptomatic onset in the NPC brain. These findings shed new light on the function of APP as a cytoprotective modulator in the CNS, offering potential evidence-based therapies against NPC.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Doença de Niemann-Pick Tipo C/metabolismo , Doença de Niemann-Pick Tipo C/patologia , Animais , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Camundongos Knockout
2.
Haematologica ; 101(4): 417-26, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26611474

RESUMO

Thymic stromal lymphopoietin (TSLP) stimulates in-vitro proliferation of human fetal B-cell precursors. However, its in-vivo role during normal human B lymphopoiesis is unknown. Genetic alterations that cause overexpression of its receptor component, cytokine receptor-like factor 2 (CRLF2), lead to high-risk B-cell acute lymphoblastic leukemia implicating this signaling pathway in leukemogenesis. We show that mouse thymic stromal lymphopoietin does not stimulate the downstream pathways (JAK/STAT5 and PI3K/AKT/mTOR) activated by the human cytokine in primary high-risk leukemia with overexpression of the receptor component. Thus, the utility of classic patient-derived xenografts for in-vivo studies of this pathway is limited. We engineered xenograft mice to produce human thymic stromal lymphopoietin (+T mice) by injection with stromal cells transduced to express the cytokine. Control (-T) mice were produced using stroma transduced with control vector. Normal levels of human thymic stromal lymphopoietin were achieved in sera of +T mice, but were undetectable in -T mice. Patient-derived xenografts generated from +T as compared to -T mice showed a 3-6-fold increase in normal human B-cell precursors that was maintained through later stages of B-cell development. Gene expression profiles in high-risk B-cell acute lymphoblastic leukemia expanded in +T mice indicate increased mTOR pathway activation and are more similar to the original patient sample than those from -T mice. +T/-T xenografts provide a novel pre-clinical model for understanding this pathway in B lymphopoiesis and identifying treatments for high-risk B-cell acute lymphoblastic leukemia with overexpression of cytokine-like factor receptor 2.


Assuntos
Xenoenxertos/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Células Precursoras de Linfócitos B/metabolismo , Receptores de Citocinas/metabolismo , Animais , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Xenoenxertos/imunologia , Humanos , Janus Quinase 1/genética , Janus Quinase 1/metabolismo , Contagem de Linfócitos , Linfopoese/genética , Linfopoese/imunologia , Camundongos , Camundongos Transgênicos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Células Precursoras de Linfócitos B/imunologia , Células Precursoras de Linfócitos B/patologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Citocinas/genética , Proteínas Quinases S6 Ribossômicas/genética , Proteínas Quinases S6 Ribossômicas/metabolismo , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Transgenes , Transplante Heterólogo
3.
Physiol Behav ; 240: 113533, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34293404

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to memory loss and is often accompanied by increased anxiety. Although AD is a heterogeneous disease, dysregulation of inflammatory pathways is a consistent event. Interestingly, the amyloid precursor protein (APP), which is the source of the amyloid peptide Aß, is also necessary for the efficient regulation of the innate immune response. Here, we hypothesize that loss of APP function in mice would lead to cognitive loss and anxiety behavior, both of which are typically present in AD, as well as changes in the expression of inflammatory mediators. To test this hypothesis, we performed open field, Y-maze and novel object recognition tests on 12-18-week-old male and female wildtype and AppKO mice to measure thigmotaxis, short-term spatial memory and long-term recognition memory. We then performed a quantitative multiplexed immunoassay to measure levels of 32 cytokines/chemokines associated with AD and anxiety. Our results showed that AppKO mice, compared to wildtype controls, experienced increased thigmotactic behavior but no memory impairments, and this phenotype correlated with increased IP-10 and IL-13 levels. Future studies will determine whether dysregulation of these inflammatory mediators contributes to pathogenesis in AD.


Assuntos
Doença de Alzheimer , Precursor de Proteína beta-Amiloide , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/metabolismo , Quimiocina CXCL10/genética , Modelos Animais de Doenças , Feminino , Interleucina-13 , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
4.
Behav Brain Res ; 393: 112779, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32585301

RESUMO

Alzheimer's disease (AD) is a neurodegenerative condition associated with loss of memory function, depression and anxiety. The etiology of AD is poorly understood, but both cholesterol dyshomeostasis and dysregulation of the immune system are contributing factors. Current evidence is consistent with a detrimental effect of excess cholesterol on neuroinflammation, both in mouse models of memory loss and in dementia in humans. However, whether the impact of cholesterol on neuroinflammation occurs early and contributes to pathogenesis of the disease or simply reflects a pleiotropic impact at advanced stages of disease is unclear. To explore this question, we measured, in 9-13 week-old mice, cognitive status and changes in brain inflammatory mediators in response to a short-term high-cholesterol diet. We hypothesized that short-term exposure to excess dietary cholesterol would alter the early inflammatory responses associated with cognitive and/or behavioral impairment. We report that short-term exposure to a high-cholesterol diet led to decreased thigmotaxis and short-term spatial memory impairment without affecting long-term recognition memory. Furthermore, cognitive and behavioral phenotypes in these mice were associated with a reduction in interleukin-15 levels in the absence of changes in other inflammatory mediators. Our findings indicate that interleukin-15 may play a role in early stages of cognitive impairment secondary to hypercholesterolemia. Consequently, optimization of interleukin-15 signaling may be a viable effective cognitive therapy in the population susceptible to developing dementia due to risk factors associated with cholesterol dysregulation.


Assuntos
Colesterol na Dieta/administração & dosagem , Encefalite/metabolismo , Interleucina-15/metabolismo , Transtornos da Memória/metabolismo , Animais , Regulação para Baixo , Encefalite/induzido quimicamente , Mediadores da Inflamação/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos
5.
Neurosci Lett ; 706: 43-50, 2019 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-31067492

RESUMO

Niemann-Pick disease type C (NPC) is a fatal neurodegenerative condition with no FDA-approved therapy. Previous studies demonstrated that neuroinflammation is an early pathologic event and a disease modifier of NPC, affecting symptomatic onset and overall lifespan. Therefore, NPC-specific anti-inflammatory therapy may result in clinical benefit. However, to date, the initial trigger of the inflammatory onset and the mechanism driving the sustained chronic neuroinflammation remain unknown. In this study, we utilized a genome-wide transcriptome analysis to identify the key pathways involved in early NPC. Our results showed that an atypical pattern of interferon downstream signaling that involves both IFN-γ- and IFN-α-responsive genes is activated in pre-symptomatic Npc1-/- cerebella. Functional analysis of the differentially expressed genes highlighted microglial activation, anti-viral response, and T-lymphocyte activation and chemotaxis pathways. Multiplex protein analysis confirmed that a potent IFN-γ-responsive cytokine, IP-10/CXCL10 was significantly upregulated in the pre-symptomatic stage and further exacerbated in the terminal stage. In addition, several IFN-γ-responsive cytokines were elevated in the terminal stage Npc1-/- cerebella, including MIG/CXCL9, MCP-1/CCL2, MIP-1α/CCL3, MIP-1ß/CCL4, RANTES/CCL5, M-CSF, and IL-1α. Together, our results describe a novel activation pattern of interferon downstream signaling in pre-symptomatic NPC, as well as key inflammatory mediators that could serve as potential targets for NPC-specific anti-inflammatory therapy.


Assuntos
Cerebelo/metabolismo , Interferons/metabolismo , Doença de Niemann-Pick Tipo C/metabolismo , Transdução de Sinais/genética , Animais , Citocinas/metabolismo , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Interferons/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Camundongos Knockout , Proteína C1 de Niemann-Pick , Doença de Niemann-Pick Tipo C/genética , Sintomas Prodrômicos
6.
Sci Rep ; 7(1): 13898, 2017 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-29066835

RESUMO

The function of the amyloid precursor protein (APP) in brain health remains unclear. This study elucidated a novel cytoprotective signaling pathway initiated by the APP transcriptionally active intracellular domain (AICD) in response to 27-hydroxycholesterol (27OHC), an oxidized cholesterol metabolite associated with neurodegeneration. The cellular response to 27OHC was hormetic, such that low, but not high, doses promoted AICD transactivation of microtubule associated serine/threonine kinase family member 4 (MAST4). MAST4 in turn phosphorylated and inhibited FOXO1-dependent transcriptional repression of rhotekin 2 (RTKN2), an oxysterol stress responder, to optimize cell survival. A palmitate-rich diet, which increases serum 27OHC, or APP ablation, abrogated this response in vivo. Further, this pathway was downregulated in human Alzheimer's Disease (AD) brains but not in frontotemporal dementia brains. These results unveil MAST4 as functional kinase of FOXO1 in a 27OHC AICD-driven, hormetic pathway providing insight for therapeutic approaches against cholesterol associated neuronal disorders.


Assuntos
Precursor de Proteína beta-Amiloide/genética , Hormese , Hidroxicolesteróis/farmacologia , Espaço Intracelular/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transcrição Gênica/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Linhagem Celular Tumoral , Proteína Forkhead Box O1/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Espaço Intracelular/metabolismo , Masculino , Camundongos , Fosforilação/efeitos dos fármacos , Ratos
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