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1.
Immunity ; 57(1): 86-105.e9, 2024 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-38159572

RESUMO

Triggering receptor expressed on myeloid cells 2 (Trem2) is a myeloid cell-specific gene expressed in brain microglia, with variants that are associated with neurodegenerative diseases, including Alzheimer's disease. Trem2 is essential for microglia-mediated synaptic refinement, but whether Trem2 contributes to shaping neuronal development remains unclear. Here, we demonstrate that Trem2 plays a key role in controlling the bioenergetic profile of pyramidal neurons during development. In the absence of Trem2, developing neurons in the hippocampal cornus ammonis (CA)1 but not in CA3 subfield displayed compromised energetic metabolism, accompanied by reduced mitochondrial mass and abnormal organelle ultrastructure. This was paralleled by the transcriptional rearrangement of hippocampal pyramidal neurons at birth, with a pervasive alteration of metabolic, oxidative phosphorylation, and mitochondrial gene signatures, accompanied by a delay in the maturation of CA1 neurons. Our results unveil a role of Trem2 in controlling neuronal development by regulating the metabolic fitness of neurons in a region-specific manner.


Assuntos
Doença de Alzheimer , Microglia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Metabolismo Energético , Microglia/metabolismo , Neurônios/metabolismo , Animais , Camundongos
2.
EMBO J ; 41(23): e111192, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36314682

RESUMO

Intracerebral hemorrhages are recognized risk factors for neurodevelopmental disorders and represent early biomarkers for cognitive dysfunction and mental disability, but the pathways leading to their occurrence are not well defined. We report that a single intrauterine exposure of the immunostimulant Poly I:C to pregnant mice at gestational day 9, which models a prenatal viral infection and the consequent maternal immune activation, induces the defective formation of brain vessels and causes intracerebral hemorrhagic events, specifically in male offspring. We demonstrate that maternal immune activation promotes the production of the TGF-ß1 active form and the consequent enhancement of pSMAD1-5 in males' brain endothelial cells. TGF-ß1, in combination with IL-1ß, reduces the endothelial expression of CD146 and claudin-5, alters the endothelium-pericyte interplay resulting in low pericyte coverage, and increases hemorrhagic events in the adult offspring. By showing that exposure to Poly I:C at the beginning of fetal cerebral angiogenesis results in sex-specific alterations of brain vessels, we provide a mechanistic framework for the association between intragravidic infections and anomalies of the neural vasculature, which may contribute to neuropsychiatric disorders.


Assuntos
Hemorragia Cerebral , Efeitos Tardios da Exposição Pré-Natal , Animais , Feminino , Masculino , Camundongos , Gravidez , Comportamento Animal , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Hemorragia Cerebral/patologia , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Poli I-C/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/patologia , Fator de Crescimento Transformador beta1/metabolismo
3.
EMBO J ; 39(16): e105380, 2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32657463

RESUMO

Neuronal circuit assembly requires the fine balance between synapse formation and elimination. Microglia, through the elimination of supernumerary synapses, have an established role in this process. While the microglial receptor TREM2 and the soluble complement proteins C1q and C3 are recognized as key players, the neuronal molecular components that specify synapses to be eliminated are still undefined. Here, we show that exposed phosphatidylserine (PS) represents a neuronal "eat-me" signal involved in microglial-mediated pruning. In hippocampal neuron and microglia co-cultures, synapse elimination can be partially prevented by blocking accessibility of exposed PS using Annexin V or through microglial loss of TREM2. In vivo, PS exposure at both hippocampal and retinogeniculate synapses and engulfment of PS-labeled material by microglia occurs during established developmental periods of microglial-mediated synapse elimination. Mice deficient in C1q, which fail to properly refine retinogeniculate connections, have elevated presynaptic PS exposure and reduced PS engulfment by microglia. These data provide mechanistic insight into microglial-mediated synapse pruning and identify a novel role of developmentally regulated neuronal PS exposure that is common among developing brain structures.


Assuntos
Hipocampo/metabolismo , Microglia/metabolismo , Neurônios/metabolismo , Fosfatidilserinas/metabolismo , Sinapses/metabolismo , Animais , Técnicas de Cocultura , Complemento C1q/genética , Complemento C1q/metabolismo , Complemento C3/genética , Complemento C3/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Fosfatidilserinas/genética , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Sinapses/genética
5.
Clin Immunol ; 173: 133-146, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27720845

RESUMO

Multiple Sclerosis (MS) is an inflammatory disease with neurodegenerative alterations, ultimately progressing to neurological handicap. Therapies are effective in counteracting inflammation but not neurodegeneration. Biomarkers predicting disease course or treatment response are lacking. We investigated whether altered gene and protein expression profiles were detectable in the peripheral blood of 78 relapsing remitting MS (RR-MS) patients treated by disease-modifying therapies. A discovery/validation study on RR-MS responsive to glatiramer acetate identified 8 differentially expressed genes: ITGA2B, ITGB3, CD177, IGJ, IL5RA, MMP8, P2RY12, and S100ß. A longitudinal study on glatiramer acetate, Interferon-ß, or Fingolimod treated RR-MS patients confirmed that 7 out of 8 genes were downregulated with reference to the different therapies, whereas S100ß was always upregulated. Thus, we identified a peripheral gene signature associated with positive response in RR-MS which may also explain drug immunomodulatory effects. The usefulness of this signature as a biomarker needs confirmation on larger series of patients.


Assuntos
Fatores Imunológicos/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/genética , Transcriptoma/efeitos dos fármacos , Adulto , Feminino , Cloridrato de Fingolimode/uso terapêutico , Perfilação da Expressão Gênica , Acetato de Glatiramer/uso terapêutico , Humanos , Interferon beta/uso terapêutico , Leucócitos Mononucleares/metabolismo , Masculino , Esclerose Múltipla Recidivante-Remitente/sangue , Adulto Jovem
6.
Immunobiology ; 221(11): 1227-36, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27387891

RESUMO

Myasthenia gravis (MG) is a T-cell dependent autoimmune disorder of the neuromuscular junction, characterised by muscle weakness and fatigability. Autoimmunity is thought to initiate in the thymus of acetylcholine receptor (AChR)-positive MG patients; however, the molecular mechanisms linking intra-thymic MG pathogenesis with autoreactivity via the circulation to the muscle target organ are poorly understood. Using whole-transcriptome sequencing, we compared the transcriptional profile of peripheral blood mononuclear cells from AChR-early onset MG (AChR-EOMG) patients with healthy controls: 178 coding transcripts and 229 long non-coding RNAs, including 11 pre-miRNAs, were differentially expressed. Among the 178 coding transcripts, 128 were annotated of which 17% were associated with the 'infectious disease' functional category and 46% with 'inflammatory disease' and 'inflammatory response-associated' categories. Validation of selected transcripts by qPCR indicated that of the infectious disease-related transcripts, ETF1, NFKB2, PLK3, and PPP1R15A were upregulated, whereas CLC and IL4 were downregulated in AChR-EOMG patients; in the 'inflammatory' categories, ABCA1, FUS, and RELB were upregulated, suggesting a contribution of these molecules to immunological dysfunctions in MG. Data selection and validation were also based on predicted microRNA-mRNA interactions. We found that miR-612, miR-3654, and miR-3651 were increased, whereas miR-612-putative AKAp12 and HRH4 targets and the miR-3651-putative CRISP3 target were downregulated in AChR-EOMG, also suggesting altered immunoregulation. Our findings reveal a novel peripheral molecular signature in AChR-EOMG, reflecting a critical involvement of inflammatory- and infectious disease-related immune responses in disease pathogenesis.


Assuntos
Infecções/complicações , Inflamação/complicações , Leucócitos Mononucleares/metabolismo , Miastenia Gravis/etiologia , Adulto , Fatores Etários , Idade de Início , Biomarcadores , Estudos de Casos e Controles , Análise por Conglomerados , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Infecções/etiologia , Inflamação/etiologia , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Miastenia Gravis/sangue , Miastenia Gravis/diagnóstico , RNA não Traduzido/genética , Receptores Colinérgicos/metabolismo , Transcriptoma
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