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1.
Cell ; 182(3): 625-640.e24, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32702313

RESUMO

The brain is a site of relative immune privilege. Although CD4 T cells have been reported in the central nervous system, their presence in the healthy brain remains controversial, and their function remains largely unknown. We used a combination of imaging, single cell, and surgical approaches to identify a CD69+ CD4 T cell population in both the mouse and human brain, distinct from circulating CD4 T cells. The brain-resident population was derived through in situ differentiation from activated circulatory cells and was shaped by self-antigen and the peripheral microbiome. Single-cell sequencing revealed that in the absence of murine CD4 T cells, resident microglia remained suspended between the fetal and adult states. This maturation defect resulted in excess immature neuronal synapses and behavioral abnormalities. These results illuminate a role for CD4 T cells in brain development and a potential interconnected dynamic between the evolution of the immunological and neurological systems. VIDEO ABSTRACT.


Assuntos
Encéfalo/citologia , Linfócitos T CD4-Positivos/metabolismo , Feto/citologia , Microglia/citologia , Microglia/metabolismo , Sinapses/metabolismo , Adulto , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Escala de Avaliação Comportamental , Células Sanguíneas/citologia , Células Sanguíneas/metabolismo , Encéfalo/embriologia , Encéfalo/metabolismo , Criança , Feminino , Feto/embriologia , Humanos , Lectinas Tipo C/metabolismo , Pulmão/citologia , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Neurogênese/genética , Parabiose , Células Piramidais/metabolismo , Células Piramidais/fisiologia , Análise de Célula Única , Baço/citologia , Baço/metabolismo , Sinapses/imunologia , Transcriptoma
2.
Cell Mol Life Sci ; 81(1): 47, 2024 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-38236305

RESUMO

Type 2 diabetes mellitus is a global epidemic that due to its increasing prevalence worldwide will likely become the most common debilitating health condition. Even if diabetes is primarily a metabolic disorder, it is now well established that key aspects of the pathogenesis of diabetes are associated with nervous system alterations, including deleterious chronic inflammation of neural tissues, referred here as neuroinflammation, along with different detrimental glial cell responses to stress conditions and neurodegenerative features. Moreover, diabetes resembles accelerated aging, further increasing the risk of developing age-linked neurodegenerative disorders. As such, the most common and disabling diabetic comorbidities, namely diabetic retinopathy, peripheral neuropathy, and cognitive decline, are intimately associated with neurodegeneration. As described in aging and other neurological disorders, glial cell alterations such as microglial, astrocyte, and Müller cell increased reactivity and dysfunctionality, myelin loss and Schwann cell alterations have been broadly described in diabetes in both human and animal models, where they are key contributors to chronic noxious inflammation of neural tissues within the PNS and CNS. In this review, we aim to describe in-depth the common and unique aspects underlying glial cell changes observed across the three main diabetic complications, with the goal of uncovering shared glial cells alterations and common pathological mechanisms that will enable the discovery of potential targets to limit neuroinflammation and prevent neurodegeneration in all three diabetic complications. Diabetes and its complications are already a public health concern due to its rapidly increasing incidence, and thus its health and economic impact. Hence, understanding the key role that glial cells play in the pathogenesis underlying peripheral neuropathy, retinopathy, and cognitive decline in diabetes will provide us with novel therapeutic approaches to tackle diabetic-associated neurodegeneration.


Assuntos
Diabetes Mellitus Tipo 2 , Retinopatia Diabética , Doenças do Sistema Nervoso Periférico , Animais , Humanos , Doenças Neuroinflamatórias , Neuroglia , Inflamação
3.
Glia ; 2024 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-39149866

RESUMO

Amyotrophic lateral sclerosis is a devastating neurodegenerative disease characterized by motor neuron death and distal axonopathy. Despite its clinical severity and profound impact in the patients and their families, many questions about its pathogenesis remain still unclear, including the role of Schwann cells and axon-glial signaling in disease progression. Upon axonal injury, upregulation of JUN transcription factor promotes Schwann cell reprogramming into a repair phenotype that favors axon regrowth and neuronal survival. To study the potential role of repair Schwann cells on motoneuron survival in amyotrophic lateral sclerosis, we generated a mouse line that over-expresses JUN in the Schwann cells of the SOD1G93A mutant, a mouse model of this disease. Then, we explored disease progression by evaluating survival, motor performance and histology of peripheral nerves and spinal cord of these mice. We found that Schwann cell JUN overexpression does not prevent axon degeneration neither motor neuron death in the SOD1G93A mice. Instead, it induces a partial demyelination of medium and large size axons, worsening motor performance and resulting in more aggressive disease phenotype.

4.
Immunol Cell Biol ; 101(1): 25-35, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36427276

RESUMO

The interaction between immune and stem cells has proven essential for homeostasis and regeneration in a wide range of tissues. However, because the central nervous system was long considered an immune-privileged organ, its immune-stem cell axis was not deeply investigated until recently. Research has shown that oligodendrocyte progenitor cells (OPCs), a highly abundant population of adult brain stem cells, establish bidirectional interactions with the immune system. Here, we provide an overview of the interactions that OPCs have with tissue-resident and recruited immune cells, paying particular attention to the role they play in myelin regeneration and neuroinflammation. We highlight the described role of OPCs as key active players in neuroinflammation, overriding the previous concept that OPCs are mere recipients of immune signals. Understanding the mechanisms behind this bidirectional interaction holds great potential for the development of novel therapeutic approaches limiting neuroinflammation and promoting myelin repair. A better understanding of the central nervous system's immune-stem cell axis will also be key for tackling two important features shared across neurodegenerative diseases, neuroinflammation and myelin loss.


Assuntos
Células Precursoras de Oligodendrócitos , Humanos , Células Precursoras de Oligodendrócitos/fisiologia , Oligodendroglia , Doenças Neuroinflamatórias , Sistema Nervoso Central , Células-Tronco , Diferenciação Celular
5.
BMC Neurosci ; 24(1): 21, 2023 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-36932329

RESUMO

BACKGROUND: Duchenne muscular dystrophy is a X-linked disease characterized by severe and progressive muscle weakness, alongside cognitive impairment and a range of neurobehavioral disorders secondary to brain dystrophin deficiency. Duchenne muscular dystrophy patients have reduced cerebral gray matter and altered white matter ultrastructure (detected by magnetic resonance imaging) compared to age-matched controls. METHODS: We studied the DE50-MD canine model of Duchenne muscular dystrophy, which is deficient in full length brain dystrophin (Dp427) isoforms and has a neurocognitive phenotype. Eight DE50-MD and 6 age-matched littermate wild type male dogs underwent serial brain magnetic resonance imaging from 14 to 33 months of age. RESULTS: Reduced regional gray matter was detected in DE50-MD dogs compared with wildtype, including the piriform lobe, hippocampus and cingulate gyrus. Lateral ventricle volume was larger in DE50-MD dogs. Differences did not progress over time. White matter volume did not differ between DE50-MD and wildtype dogs. There was no difference in brain nor cranial vault volume between DE50-MD and wildtype dogs. CONCLUSION: Dystrophin deficiency in the canine brain results in structural changes that likely contribute to the neurocognitive phenotype.


Assuntos
Distrofia Muscular de Duchenne , Cães , Masculino , Animais , Distrofia Muscular de Duchenne/diagnóstico por imagem , Distrofina/genética , Distrofina/metabolismo , Substância Cinzenta/patologia , Encéfalo/metabolismo , Imageamento por Ressonância Magnética
6.
Proc Natl Acad Sci U S A ; 117(30): 18018-18028, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32651278

RESUMO

CCN3 is a matricellular protein that promotes oligodendrocyte progenitor cell differentiation and myelination in vitro and ex vivo. CCN3 is therefore a candidate of interest in central nervous system (CNS) myelination and remyelination, and we sought to investigate the expression and role of CCN3 during these processes. We found CCN3 to be expressed predominantly by neurons in distinct areas of the CNS, primarily the cerebral cortex, hippocampus, amygdala, suprachiasmatic nuclei, anterior olfactory nuclei, and spinal cord gray matter. CCN3 was transiently up-regulated following demyelination in the brain of cuprizone-fed mice and spinal cord lesions of mice injected with lysolecithin. However, CCN3-/- mice did not exhibit significantly different numbers of oligodendroglia or differentiated oligodendrocytes in the healthy or remyelinating CNS, compared to WT controls. These results suggest that despite robust and dynamic expression in the CNS, CCN3 is not required for efficient myelination or remyelination in the murine CNS in vivo.


Assuntos
Sistema Nervoso Central/metabolismo , Doenças Desmielinizantes/etiologia , Regulação da Expressão Gênica , Proteína Sobre-Expressa em Nefroblastoma/genética , Remielinização/genética , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Imunofluorescência , Camundongos , Bainha de Mielina/metabolismo , Proteína Sobre-Expressa em Nefroblastoma/metabolismo , Células Precursoras de Oligodendrócitos/metabolismo , Oligodendroglia/metabolismo , Medula Espinal/metabolismo , Medula Espinal/patologia
7.
Mol Cell Proteomics ; 19(8): 1281-1302, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32434922

RESUMO

Following central nervous system (CNS) demyelination, adult oligodendrocyte progenitor cells (OPCs) can differentiate into new myelin-forming oligodendrocytes in a regenerative process called remyelination. Although remyelination is very efficient in young adults, its efficiency declines progressively with ageing. Here we performed proteomic analysis of OPCs freshly isolated from the brains of neonate, young and aged female rats. Approximately 50% of the proteins are expressed at different levels in OPCs from neonates compared with their adult counterparts. The amount of myelin-associated proteins, and proteins associated with oxidative phosphorylation, inflammatory responses and actin cytoskeletal organization increased with age, whereas cholesterol-biosynthesis, transcription factors and cell cycle proteins decreased. Our experiments provide the first ageing OPC proteome, revealing the distinct features of OPCs at different ages. These studies provide new insights into why remyelination efficiency declines with ageing and potential roles for aged OPCs in other neurodegenerative diseases.


Assuntos
Envelhecimento/metabolismo , Células Precursoras de Oligodendrócitos/metabolismo , Proteoma/metabolismo , Animais , Animais Recém-Nascidos , Biomarcadores/metabolismo , Separação Celular , Colesterol/metabolismo , Bainha de Mielina/metabolismo , Doenças Neurodegenerativas/patologia , Células Precursoras de Oligodendrócitos/citologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Dobramento de Proteína , Proteômica , Proteostase , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
8.
J Neurol Neurosurg Psychiatry ; 92(3): 295-302, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33184094

RESUMO

OBJECTIVE: To establish a rigorous, expert-led, evidence-based approach to the evaluation of licensed drugs for repurposing and testing in clinical trials of people with progressive multiple sclerosis (MS). METHODS: We long-listed licensed drugs with evidence of human safety, blood-brain barrier penetrance and demonstrable efficacy in at least one animal model, or mechanistic target, agreed by a panel of experts and people with MS to be relevant to the pathogenesis of progression. We systematically reviewed the preclinical and clinical literature for each compound, condensed this into a database of summary documents and short-listed drugs by scoring each one of them. Drugs were evaluated for immediate use in a clinical trial, and our selection was scrutinised by a final independent expert review. RESULTS: From a short list of 55 treatments, we recommended four treatments for immediate testing in progressive MS: R-α-lipoic acid, metformin, the combination treatment of R-α-lipoic acid and metformin, and niacin. We also prioritised clemastine, lamotrigine, oxcarbazepine, nimodipine and flunarizine. CONCLUSIONS: We report a standardised approach for the identification of candidate drugs for repurposing in the treatment of progressive MS.


Assuntos
Reposicionamento de Medicamentos , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Animais , Avaliação de Medicamentos , Humanos
9.
Glia ; 67(8): 1510-1525, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31038798

RESUMO

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that leads to severe neurological deficits. Due to their immunomodulatory and neuroprotective activities and their ability to promote the generation of oligodendrocytes, mesenchymal stem cells (MSCs) are currently being developed for autologous cell therapy in MS. As aging reduces the regenerative capacity of all tissues, it is of relevance to investigate whether MSCs retain their pro-oligodendrogenic activity with increasing age. We demonstrate that MSCs derived from aged rats have a reduced capacity to induce oligodendrocyte differentiation of adult CNS stem/progenitor cells. Aging also abolished the ability of MSCs to enhance the generation of myelin-like sheaths in demyelinated cerebellar slice cultures. Finally, in a rat model for CNS demyelination, aging suppressed the capability of systemically transplanted MSCs to boost oligodendrocyte progenitor cell (OPC) differentiation during remyelination. Thus, aging restricts the ability of MSCs to support the generation of oligodendrocytes and consequently inhibits their capacity to enhance the generation of myelin-like sheaths. These findings may impact on the design of therapies using autologous MSCs in older MS patients.


Assuntos
Envelhecimento/fisiologia , Células-Tronco Mesenquimais/fisiologia , Oligodendroglia/fisiologia , Remielinização/fisiologia , Animais , Células Cultivadas , Doenças Desmielinizantes/fisiopatologia , Modelos Animais de Doenças , Feminino , Masculino , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Técnicas de Cultura de Tecidos
10.
Brain ; 144(8): 2231-2233, 2021 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-34382068
11.
Brain ; 138(Pt 12): 3581-97, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26463675

RESUMO

The efficiency of central nervous system remyelination declines with age. This is in part due to an age-associated decline in the phagocytic removal of myelin debris, which contains inhibitors of oligodendrocyte progenitor cell differentiation. In this study, we show that expression of genes involved in the retinoid X receptor pathway are decreased with ageing in both myelin-phagocytosing human monocytes and mouse macrophages using a combination of in vivo and in vitro approaches. Disruption of retinoid X receptor function in young macrophages, using the antagonist HX531, mimics ageing by reducing myelin debris uptake. Macrophage-specific RXRα (Rxra) knockout mice revealed that loss of function in young mice caused delayed myelin debris uptake and slowed remyelination after experimentally-induced demyelination. Alternatively, retinoid X receptor agonists partially restored myelin debris phagocytosis in aged macrophages. The agonist bexarotene, when used in concentrations achievable in human subjects, caused a reversion of the gene expression profile in multiple sclerosis patient monocytes to a more youthful profile and enhanced myelin debris phagocytosis by patient cells. These results reveal the retinoid X receptor pathway as a positive regulator of myelin debris clearance and a key player in the age-related decline in remyelination that may be targeted by available or newly-developed therapeutics.


Assuntos
Envelhecimento/metabolismo , Envelhecimento/patologia , Bainha de Mielina/metabolismo , Fagocitose , Receptor X Retinoide alfa/metabolismo , Adulto , Animais , Benzoatos/farmacologia , Bexaroteno , Compostos de Bifenilo/farmacologia , Feminino , Humanos , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Esclerose Múltipla/metabolismo , Fagocitose/efeitos dos fármacos , Receptor X Retinoide alfa/agonistas , Receptor X Retinoide alfa/antagonistas & inibidores , Receptor X Retinoide alfa/genética , Transdução de Sinais/fisiologia , Tetra-Hidronaftalenos/farmacologia , Transcriptoma/efeitos dos fármacos , Adulto Jovem
12.
Trends Mol Med ; 29(7): 481-483, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37217360

RESUMO

Recent work from Lemaitre and colleagues leveraged a central nervous system (CNS)-specific gene delivery approach to expand regulatory T cells (Treg) in aged mice. CNS-restricted Treg expansion reversed age-related glial cell transcriptomic changes and prevented aspects of cognitive decline, unveiling immune modulation as a potential approach to protect cognitive function with age.


Assuntos
Disfunção Cognitiva , Linfócitos T Reguladores , Camundongos , Humanos , Animais , Encéfalo , Sistema Nervoso Central , Disfunção Cognitiva/terapia
13.
Br J Pharmacol ; 180(13): 1651-1673, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36965025

RESUMO

Ageing is the main risk factor common to most primary neurodegenerative disorders. Indeed, age-related brain alterations have been long considered to predispose to neurodegeneration. Although protein misfolding and the accumulation of toxic protein aggregates have been considered as causative events in neurodegeneration, several other biological pathways affected by brain ageing also contribute to pathogenesis. Here, we discuss the evidence showing the involvement of the mechanisms controlling neuronal structure, gene expression, autophagy, cell metabolism and neuroinflammation in the onset and progression of neurodegenerative disorders. Furthermore, we review the therapeutic strategies currently under development or as future approaches designed to normalize these pathways, which may then increase brain resilience to cope with toxic protein species. In addition to therapies targeting the insoluble protein aggregates specifically associated with each neurodegenerative disorder, these novel pharmacological approaches may be part of combined therapies designed to rescue brain function.


Assuntos
Doenças Neurodegenerativas , Agregados Proteicos , Humanos , Doenças Neurodegenerativas/metabolismo , Proteínas , Autofagia/fisiologia
14.
Front Aging Neurosci ; 12: 572090, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33173502

RESUMO

Neurodegenerative diseases of the central nervous system (CNS) are characterized by progressive neuronal death and neurological dysfunction, leading to increased disability and a loss of cognitive or motor functions. Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis have neurodegeneration as a primary feature. However, in other CNS diseases such as multiple sclerosis, stroke, traumatic brain injury, and spinal cord injury, neurodegeneration follows another insult, such as demyelination or ischaemia. Although there are different primary causes to these diseases, they all share a hallmark of neuroinflammation. Neuroinflammation can occur through the activation of resident immune cells such as microglia, cells of the innate and adaptive peripheral immune system, meningeal inflammation and autoantibodies directed toward components of the CNS. Despite chronic inflammation being pathogenic in these diseases, local inflammation after insult can also promote endogenous regenerative processes in the CNS, which are key to slowing disease progression. The normal aging process in the healthy brain is associated with a decline in physiological function, a steady increase in levels of neuroinflammation, brain shrinkage, and memory deficits. Likewise, aging is also a key contributor to the progression and exacerbation of neurodegenerative diseases. As there are associated co-morbidities within an aging population, pinpointing the precise relationship between aging and neurodegenerative disease progression can be a challenge. The CNS has historically been considered an isolated, "immune privileged" site, however, there is mounting evidence that adaptive immune cells are present in the CNS of both healthy individuals and diseased patients. Adaptive immune cells have also been implicated in both the degeneration and regeneration of the CNS. In this review, we will discuss the key role of the adaptive immune system in CNS degeneration and regeneration, with a focus on how aging influences this crosstalk.

15.
Front Immunol ; 10: 2171, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31572381

RESUMO

Pathogenic mechanisms of T cells in several central nervous system (CNS) disorders are well-established. However, more recent studies have uncovered compelling beneficial roles of T cells in neurological diseases, ranging from tissue protection to regeneration. These divergent functions arise due to the diversity of T cell subsets, particularly CD4+ T cells. Here, we review the beneficial impact of T cell subsets in a range of neuroinflammatory and neurodegenerative diseases including multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, and CNS trauma. Both T cell-secreted mediators and direct cell contact-dependent mechanisms deliver neuroprotective, neuroregenerative and immunomodulatory signals in these settings. Understanding the molecular details of these beneficial T cell mechanisms will provide novel targets for therapeutic exploitation that can be applied to a range of neurological disorders.


Assuntos
Doenças do Sistema Nervoso Central/imunologia , Linfócitos T/imunologia , Imunidade Adaptativa , Animais , Comportamento , Encéfalo/crescimento & desenvolvimento , Encéfalo/imunologia , Homeostase , Humanos
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