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1.
Nat Metab ; 6(8): 1479-1491, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39048800

RESUMO

Primary mitochondrial diseases (PMDs) are associated with pediatric neurological disorders and are traditionally related to oxidative phosphorylation system (OXPHOS) defects in neurons. Interestingly, both PMD mouse models and patients with PMD show gliosis, and pharmacological depletion of microglia, the innate immune cells of the brain, ameliorates multiple symptoms in a mouse model. Given that microglia activation correlates with the expression of OXPHOS genes, we studied whether OXPHOS deficits in microglia may contribute to PMDs. We first observed that the metabolic rewiring associated with microglia stimulation in vitro (via IL-33 or TAU treatment) was partially changed by complex I (CI) inhibition (via rotenone treatment). In vivo, we generated a mouse model deficient for CI activity in microglia (MGcCI). MGcCI microglia showed metabolic rewiring and gradual transcriptional activation, which led to hypertrophy and dysfunction in juvenile (1-month-old) and adult (3-month-old) stages, respectively. MGcCI mice presented widespread reactive astrocytes, a decrease of synaptic markers accompanied by an increased number of parvalbumin neurons, a behavioral deficit characterized by prolonged periods of immobility, loss of weight and premature death that was partially rescued by pharmacologic depletion of microglia. Our data demonstrate that microglia development depends on mitochondrial CI and suggest a direct microglial contribution to PMDs.


Assuntos
Complexo I de Transporte de Elétrons , Microglia , Doenças Mitocondriais , Animais , Microglia/metabolismo , Camundongos , Complexo I de Transporte de Elétrons/metabolismo , Complexo I de Transporte de Elétrons/deficiência , Complexo I de Transporte de Elétrons/genética , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/etiologia , Fosforilação Oxidativa , Mitocôndrias/metabolismo , Neurônios/metabolismo , Neuroglia/metabolismo , Modelos Animais de Doenças , Astrócitos/metabolismo , Gliose/metabolismo , Gliose/patologia , Encéfalo/metabolismo , Encéfalo/patologia
2.
Cells Dev ; 174: 203841, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37060947

RESUMO

In the adult rodent brain, neural stem cells (NSCs) reside in the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the hippocampus. In these areas, NSCs and their progeny integrate intrinsic signals and extrinsic cues provided by their microenvironment that control their behavior. The vasculature in the SVZ and SGZ, and the choroid plexus (ChP) in the SVZ, have emerged as critical compartments of the neurogenic niches as they provide a rich repertoire of cues to regulate NSC quiescence, proliferation, self-renewal and differentiation. Physical contact between NSCs and blood vessels is also a feature within the niches and supports different processes such as quiescence, migration and vesicle transport. In this review, we provide a description of the brain and choroid plexus vasculature in both stem cell niches, highlighting the main properties and role of the vasculature in each niche. We also summarize the current understanding of how blood vessel- and ChP-derived signals influence the behavior of NSCs in physiological adulthood, as well as upon aging.


Assuntos
Células-Tronco Neurais , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Encéfalo , Ventrículos Laterais/fisiologia , Diferenciação Celular
3.
Nat Neurosci ; 26(2): 226-238, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36624276

RESUMO

Vaccines against SARS-CoV-2 have been shown to be safe and effective but their protective efficacy against infection in the brain is yet unclear. Here, in the susceptible transgenic K18-hACE2 mouse model of severe coronavirus disease 2019 (COVID-19), we report a spatiotemporal description of SARS-CoV-2 infection and replication through the brain. SARS-CoV-2 brain replication occurs primarily in neurons, leading to neuronal loss, signs of glial activation and vascular damage in mice infected with SARS-CoV-2. One or two doses of a modified vaccinia virus Ankara (MVA) vector expressing the SARS-CoV-2 spike (S) protein (MVA-CoV2-S) conferred full protection against SARS-CoV-2 cerebral infection, preventing virus replication in all areas of the brain and its associated damage. This protection was maintained even after SARS-CoV-2 reinfection. These findings further support the use of MVA-CoV2-S as a promising vaccine candidate against SARS-CoV-2/COVID-19.


Assuntos
COVID-19 , SARS-CoV-2 , Camundongos , Animais , Humanos , Camundongos Transgênicos , Vacinas contra COVID-19 , Encéfalo
4.
Nat Aging ; 1(4): 385-399, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-37117599

RESUMO

Genetic Alzheimer's disease (AD) risk factors associate with reduced defensive amyloid ß plaque-associated microglia (AßAM), but the contribution of modifiable AD risk factors to microglial dysfunction is unknown. In AD mouse models, we observe concomitant activation of the hypoxia-inducible factor 1 (HIF1) pathway and transcription of mitochondrial-related genes in AßAM, and elongation of mitochondria, a cellular response to maintain aerobic respiration under low nutrient and oxygen conditions. Overactivation of HIF1 induces microglial quiescence in cellulo, with lower mitochondrial respiration and proliferation. In vivo, overstabilization of HIF1, either genetically or by exposure to systemic hypoxia, reduces AßAM clustering and proliferation and increases Aß neuropathology. In the human AD hippocampus, upregulation of HIF1α and HIF1 target genes correlates with reduced Aß plaque microglial coverage and an increase of Aß plaque-associated neuropathology. Thus, hypoxia (a modifiable AD risk factor) hijacks microglial mitochondrial metabolism and converges with genetic susceptibility to cause AD microglial dysfunction.


Assuntos
Doença de Alzheimer , Hipóxia Celular , Fator 1 Induzível por Hipóxia , Microglia , Mitocôndrias , Doença de Alzheimer/fisiopatologia , Mitocôndrias/metabolismo , Microglia/metabolismo , Fator 1 Induzível por Hipóxia/metabolismo , Peptídeos beta-Amiloides/metabolismo , Hipocampo , Fatores de Risco , Animais , Camundongos , Humanos , Linhagem Celular , Fosforilação Oxidativa
5.
Nat Commun ; 12(1): 3098, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34035282

RESUMO

The human Alzheimer's disease (AD) brain accumulates angiogenic markers but paradoxically, the cerebral microvasculature is reduced around Aß plaques. Here we demonstrate that angiogenesis is started near Aß plaques in both AD mouse models and human AD samples. However, endothelial cells express the molecular signature of non-productive angiogenesis (NPA) and accumulate, around Aß plaques, a tip cell marker and IB4 reactive vascular anomalies with reduced NOTCH activity. Notably, NPA induction by endothelial loss of presenilin, whose mutations cause familial AD and which activity has been shown to decrease with age, produced a similar vascular phenotype in the absence of Aß pathology. We also show that Aß plaque-associated NPA locally disassembles blood vessels, leaving behind vascular scars, and that microglial phagocytosis contributes to the local loss of endothelial cells. These results define the role of NPA and microglia in local blood vessel disassembly and highlight the vascular component of presenilin loss of function in AD.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Vasos Sanguíneos/metabolismo , Encéfalo/metabolismo , Neovascularização Patológica/genética , Placa Amiloide/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Vasos Sanguíneos/patologia , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neovascularização Patológica/metabolismo , Placa Amiloide/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos
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