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1.
Neurobiol Dis ; 186: 106263, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37591465

RESUMO

The R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2) increases the risk of Alzheimer's disease (AD). To investigate potential mechanisms, we analyzed knockin mice expressing human TREM2-R47H from one mutant mouse Trem2 allele. TREM2-R47H mice showed increased seizure activity in response to an acute excitotoxin challenge, compared to wildtype controls or knockin mice expressing the common variant of human TREM2. TREM2-R47H also increased spontaneous thalamocortical epileptiform activity in App knockin mice expressing amyloid precursor proteins bearing autosomal dominant AD mutations and a humanized amyloid-ß sequence. In mice with or without such App modifications, TREM2-R47H increased the density of putative synapses in cortical regions without amyloid plaques. TREM2-R47H did not affect synaptic density in hippocampal regions with or without plaques. We conclude that TREM2-R47H increases AD-related network hyperexcitability and that it may do so, at least in part, by causing an imbalance in synaptic densities across brain regions.


Assuntos
Doença de Alzheimer , Humanos , Animais , Camundongos , Doença de Alzheimer/genética , Alelos , Convulsões , Peptídeos beta-Amiloides , Modelos Animais de Doenças , Placa Amiloide , Sinapses , Glicoproteínas de Membrana/genética , Receptores Imunológicos/genética
2.
Sci Transl Med ; 13(622): eabe3947, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34851693

RESUMO

The hemizygous R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), a microglia-specific gene in the brain, increases risk for late-onset Alzheimer's disease (AD). Using transcriptomic analysis of single nuclei from brain tissues of patients with AD carrying the R47H mutation or the common variant (CV)­TREM2, we found that R47H-associated microglial subpopulations had enhanced inflammatory signatures reminiscent of previously identified disease-associated microglia (DAM) and hyperactivation of AKT, one of the signaling pathways downstream of TREM2. We established a tauopathy mouse model with heterozygous knock-in of the human TREM2 with the R47H mutation or CV and found that R47H induced and exacerbated TAU-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had substantial overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of AKT signaling, and elevation of a subset of DAM signatures. Pharmacological AKT inhibition with MK-2206 largely reversed the enhanced inflammatory signatures in primary R47H microglia treated with TAU fibrils. In R47H heterozygous tauopathy mice, MK-2206 treatment abolished a tauopathy-dependent microglial subcluster and rescued tauopathy-induced synapse loss. By uncovering disease-enhancing mechanisms of the R47H mutation conserved in human and mouse, our study supports inhibitors of AKT signaling as a microglial modulating strategy to treat AD.


Assuntos
Doença de Alzheimer , Microglia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Animais , Encéfalo/metabolismo , Feminino , Humanos , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Microglia/metabolismo , Mutação/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Imunológicos/metabolismo
3.
Sci Rep ; 10(1): 13688, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792571

RESUMO

Patients with frontotemporal dementia (FTD) resulting from granulin (GRN) haploinsufficiency have reduced levels of progranulin and exhibit dysregulation in inflammatory and lysosomal networks. Microglia produce high levels of progranulin, and reduction of progranulin in microglia alone is sufficient to recapitulate inflammation, lysosomal dysfunction, and hyperproliferation in a cell-autonomous manner. Therefore, targeting microglial dysfunction caused by progranulin insufficiency represents a potential therapeutic strategy to manage neurodegeneration in FTD. Limitations of current progranulin-enhancing strategies necessitate the discovery of new targets. To identify compounds that can reverse microglial defects in Grn-deficient mouse microglia, we performed a compound screen coupled with high throughput sequencing to assess key transcriptional changes in inflammatory and lysosomal pathways. Positive hits from this initial screen were then further narrowed down based on their ability to rescue cathepsin activity, a critical biochemical readout of lysosomal capacity. The screen identified nor-binaltorphimine dihydrochloride (nor-BNI) and dibutyryl-cAMP, sodium salt (DB-cAMP) as two phenotypic modulators of progranulin deficiency. In addition, nor-BNI and DB-cAMP also rescued cell cycle abnormalities in progranulin-deficient cells. These data highlight the potential of a transcription-based platform for drug screening, and advance two novel lead compounds for FTD.


Assuntos
Bucladesina/farmacologia , Cisteína Proteases/metabolismo , Demência Frontotemporal/genética , Perfilação da Expressão Gênica/métodos , Microglia/citologia , Naltrexona/análogos & derivados , Progranulinas/deficiência , Animais , Ciclo Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Demência Frontotemporal/tratamento farmacológico , Demência Frontotemporal/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Inativação de Genes , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lisossomos/genética , Lisossomos/metabolismo , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Modelos Biológicos , Naltrexona/farmacologia , Análise de Sequência de RNA , Bibliotecas de Moléculas Pequenas/farmacologia
4.
Nat Neurosci ; 23(2): 167-171, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31873194

RESUMO

Sex is a key modifier of neurological disease outcomes. Microglia are implicated in neurological diseases and modulated by microRNAs, but it is unknown whether microglial microRNAs have sex-specific influences on disease. We show in mice that microglial microRNA expression differs in males and females and that loss of microRNAs leads to sex-specific changes in the microglial transcriptome and tau pathology. These findings suggest that microglial microRNAs influence tau pathogenesis in a sex-specific manner.


Assuntos
Encéfalo/patologia , MicroRNAs/metabolismo , Microglia/metabolismo , Caracteres Sexuais , Tauopatias/patologia , Animais , Encéfalo/metabolismo , Feminino , Masculino , Camundongos , Microglia/patologia , Tauopatias/metabolismo , Transcriptoma , Proteínas tau/metabolismo
5.
Proc Natl Acad Sci U S A ; 115(40): 10172-10177, 2018 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-30232263

RESUMO

Alzheimer's disease (AD), the most common form of dementia, is characterized by the abnormal accumulation of amyloid plaques and hyperphosphorylated tau aggregates, as well as microgliosis. Hemizygous missense variants in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) are associated with elevated risk for developing late-onset AD. These variants are hypothesized to result in loss of function, mimicking TREM2 haploinsufficiency. However, the consequences of TREM2 haploinsufficiency on tau pathology and microglial function remain unknown. We report the effects of partial and complete loss of TREM2 on microglial function and tau-associated deficits. In vivo imaging revealed that microglia from aged TREM2-haploinsufficient mice show a greater impairment in their injury response compared with microglia from aged TREM2-KO mice. In transgenic mice expressing mutant human tau, TREM2 haploinsufficiency, but not complete loss of TREM2, increased tau pathology. In addition, whereas complete TREM2 deficiency protected against tau-mediated microglial activation and atrophy, TREM2 haploinsufficiency elevated expression of proinflammatory markers and exacerbated atrophy at a late stage of disease. The differential effects of partial and complete loss of TREM2 on microglial function and tau pathology provide important insights into the critical role of TREM2 in AD pathogenesis.


Assuntos
Doença de Alzheimer , Haploinsuficiência , Hemizigoto , Glicoproteínas de Membrana , Microglia/metabolismo , Mutação de Sentido Incorreto , Receptores Imunológicos , Envelhecimento/genética , Envelhecimento/metabolismo , Envelhecimento/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Microglia/patologia , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo
6.
Neuron ; 97(5): 991-993, 2018 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-29518360

RESUMO

Mutations in TREM2 increase risk for late-onset AD. In this issue of Neuron, Zhao et al. (2018) show that TREM2 binds Aß to enhance its clearance and Lee et al. (2018) demonstrate that human TREM2 expression in AD mice ameliorates Aß-associated deficits.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Animais , Dosagem de Genes , Humanos , Glicoproteínas de Membrana/genética , Camundongos , Microglia , Fenótipo , Receptores Imunológicos/genética
7.
Glia ; 64(10): 1788-94, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27246804

RESUMO

Minocycline, a second generation broad-spectrum antibiotic, has been frequently postulated to be a "microglia inhibitor." A considerable number of publications have used minocycline as a tool and concluded, after achieving a pharmacological effect, that the effect must be due to "inhibition" of microglia. It is, however, unclear how this "inhibition" is achieved at the molecular and cellular levels. Here, we weigh the evidence whether minocycline is indeed a bona fide microglia inhibitor and discuss how data generated with minocycline should be interpreted. GLIA 2016;64:1788-1794.


Assuntos
Antibacterianos/farmacologia , Microglia/efeitos dos fármacos , Minociclina/farmacologia , Animais , Antibacterianos/uso terapêutico , Bases de Dados Factuais/estatística & dados numéricos , Humanos , Microglia/fisiologia , Minociclina/uso terapêutico
8.
Glia ; 64(10): 1710-32, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27100611

RESUMO

While histological changes in microglia have long been recognized as a pathological feature of Alzheimer's disease (AD), recent genetic association studies have also strongly implicated microglia in the etiology of the disease. Coding and noncoding polymorphisms in several genes expressed in microglia-including APOE, TREM2, CD33, GRN, and IL1RAP-alter AD risk, and therefore could be considered as entry points for therapeutic intervention. Furthermore, microglia may have a substantial effect on current amyloid ß (Aß) and tau immunotherapy approaches, since they are the primary cell type in the brain to mediate Fc receptor-facilitated antibody effector function. In this review, we discuss the considerations in selecting microglial therapeutic targets from the perspective of drug discovery feasibility, and consider the role of microglia in ongoing immunotherapy clinical strategies. GLIA 2016;64:1710-1732.


Assuntos
Doença de Alzheimer , Imunoterapia/métodos , Microglia/fisiologia , Doença de Alzheimer/imunologia , Doença de Alzheimer/patologia , Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/imunologia , Animais , Anticorpos/uso terapêutico , Humanos , Receptores Fc/imunologia , Proteínas tau/imunologia
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