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1.
Immunity ; 56(8): 1794-1808.e8, 2023 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-37442133

RESUMO

Triggering receptor expressed on myeloid cells 2 (TREM2) is strongly linked to Alzheimer's disease (AD) risk, but its functions are not fully understood. Here, we found that TREM2 specifically attenuated the activation of classical complement cascade via high-affinity binding to its initiator C1q. In the human AD brains, the formation of TREM2-C1q complexes was detected, and the increased density of the complexes was associated with lower deposition of C3 but higher amounts of synaptic proteins. In mice expressing mutant human tau, Trem2 haploinsufficiency increased complement-mediated microglial engulfment of synapses and accelerated synaptic loss. Administration of a 41-amino-acid TREM2 peptide, which we identified to be responsible for TREM2 binding to C1q, rescued synaptic impairments in AD mouse models. We thus demonstrate a critical role for microglial TREM2 in restricting complement-mediated synaptic elimination during neurodegeneration, providing mechanistic insights into the protective roles of TREM2 against AD pathogenesis.


Assuntos
Doença de Alzheimer , Complemento C1q , Camundongos , Animais , Humanos , Complemento C1q/genética , Complemento C1q/metabolismo , Encéfalo/metabolismo , Sinapses/metabolismo , Ativação do Complemento , Microglia/metabolismo , Doença de Alzheimer/complicações , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo
2.
J Neurochem ; 168(6): 1060-1079, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38308496

RESUMO

Neuronal hyperactivity induced by ß-amyloid (Aß) is an early pathological feature in Alzheimer's disease (AD) and contributes to cognitive decline in AD progression. However, the underlying mechanisms are still unclear. Here, we revealed that Aß increased the expression level of synaptic adhesion molecule protocadherin-γC5 (Pcdh-γC5) in a Ca2+-dependent manner, associated with aberrant elevation of synapses in both Aß-treated neurons in vitro and the cortex of APP/PS1 mice in vivo. By using Pcdhgc5 gene knockout mice, we demonstrated the critical function of Pcdh-γC5 in regulating neuronal synapse formation, synaptic transmission, and cognition. To further investigate the role of Pcdh-γC5 in AD pathogenesis, the aberrantly enhanced expression of Pcdh-γC5 in the brain of APP/PS1 mice was knocked down by shRNA. Downregulation of Pcdh-γC5 efficiently rescued neuronal hyperactivity and impaired cognition in APP/PS1 mice. Our findings revealed the pathophysiological role of Pcdh-γC5 in mediating Aß-induced neuronal hyperactivity and cognitive deficits in AD and identified a novel mechanism underlying AD pathogenesis.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Caderinas , Camundongos Knockout , Neurônios , Animais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Caderinas/metabolismo , Caderinas/genética , Camundongos , Neurônios/metabolismo , Camundongos Transgênicos , Sinapses/metabolismo , Sinapses/patologia , Proteínas Relacionadas a Caderinas , Camundongos Endogâmicos C57BL , Masculino , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/genética , Células Cultivadas , Transtornos Cognitivos/metabolismo
3.
BMC Anesthesiol ; 24(1): 77, 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38408913

RESUMO

BACKGROUND: Extensive metastatic and refractory cancer pain is common, and exhibits a dissatisfactory response to the conventional intrathecal infusion of opioid analgesics. CASE PRESENTATION: The present study reports a case of an extensive metastatic esophageal cancer patient with severe intractable pain, who underwent translumbar subarachnoid puncture with intrathecal catheterization to the prepontine cistern. After continuous infusion of low-dose morphine, the pain was well-controlled with a decrease in the numeric rating scale (NRS) of pain score from 9 to 0, and the few adverse reactions to the treatment disappeared at a low dose of morphine. CONCLUSIONS: The patient achieved a good quality of life during the one-month follow-up period.


Assuntos
Dor do Câncer , Neoplasias , Dor Intratável , Humanos , Morfina , Dor Intratável/etiologia , Dor Intratável/induzido quimicamente , Dor do Câncer/tratamento farmacológico , Qualidade de Vida , Analgésicos Opioides , Injeções Espinhais/efeitos adversos
4.
J Neurosci ; 42(25): 4958-4979, 2022 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-35606143

RESUMO

Synaptic abnormality is an important pathologic feature of autism spectrum disorders (ASDs) and responsible for various behavioral defects in these neurodevelopmental disorders. Microglia are the major immune cells in the brain and also play an important role in synapse refinement. Although dysregulated synaptic pruning by microglia during the brain development has been associated with ASDs, the underlying mechanism has yet to be fully elucidated. Herein, we observed that expression of Transmembrane protein 59 (TMEM59), a protein recently shown to regulate microglial function, was decreased in autistic patients. Furthermore, we found that both male and female mice with either complete or microglia-specific loss of Tmem59 developed ASD-like behaviors. Microglial TMEM59-deficient mice also exhibited enhanced excitatory synaptic transmission, increased dendritic spine density, and elevated levels of excitatory synaptic proteins in synaptosomes. TMEM59-deficient microglia had impaired capacity for synapse engulfment both in vivo and in vitro. Moreover, we demonstrated that TMEM59 interacted with the C1q receptor CD93 and TMEM59 deficiency promoted CD93 protein degradation in microglia. Downregulation of CD93 in microglia also impaired synapse engulfment. These findings identify a crucial role of TMEM59 in modulating microglial function on synapse refinement during brain development and suggest that TMEM59 deficiency may contribute to ASDs through disrupting phagocytosis of excitatory synapse and thus distorting the excitatory-inhibitory (E/I) neuronal activity balance.SIGNIFICANCE STATEMENT Microglia play an important role in synapse refinement. Dysregulated synaptic pruning by microglia during brain development has been associated with autism spectrum disorders (ASDs). However, the underlying mechanism has yet to be fully elucidated. Herein, we observe that the expression of Transmembrane protein 59 (TMEM59), an autophagy-related protein, is decreased in autistic patients. Moreover, we find ASD-like behaviors in mice with complete loss and with microglia-specific loss of Tmem59 Mechanistic studies reveal that TMEM59 deficiency in microglia impairs their synapse engulfment ability likely through destabilizing the C1q receptor CD93, thereby leading to enhanced excitatory neurotransmission and increased dendritic spine density. Our findings demonstrate a crucial role of microglial TMEM59 in early neuronal development and provide new insight into the etiology of ASDs.


Assuntos
Transtorno Autístico , Microglia , Animais , Transtorno Autístico/genética , Transtorno Autístico/metabolismo , Feminino , Humanos , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Microglia/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Plasticidade Neuronal/fisiologia , Fagocitose , Sinapses/fisiologia
5.
J Cell Mol Med ; 27(9): 1214-1226, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36977207

RESUMO

Duplications of the Xq28 region are a common cause of X-linked intellectual disability (XLID). The RAB39B gene locates in Xq28 and has been implicated in disease pathogenesis. However, whether increased dosage of RAB39B leads to cognitive impairment and synaptic dysfunction remains elusive. Herein, we overexpressed RAB39B in mouse brain by injecting AAVs into bilateral ventricles of neonatal animals. We found that at 2 months of age, neuronal overexpression of RAB39B impaired the recognition memory and the short-term working memory in mice and resulted in certain autism-like behaviours, including social novelty defect and repetitive grooming behaviour in female mice. Moreover, overexpression of RAB39B decreased dendritic arborization of primary neurons in vitro and reduced synaptic transmission in female mice. Neuronal overexpression of RAB39B also altered autophagy without affecting levels and PSD distribution of synaptic proteins. Our results demonstrate that overexpression of RAB39B compromises normal neuronal development, thereby resulting in dysfunctional synaptic transmission and certain intellectual disability and behavioural abnormalities in mice. These findings identify a molecular mechanism underlying XLID with increased copy numbers of Xq28 and provide potential strategies for disease intervention.


Assuntos
Transtorno Autístico , Deficiência Intelectual , Animais , Camundongos , Feminino , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Neurônios/metabolismo , Transtorno Autístico/genética , Transmissão Sináptica , Animais Recém-Nascidos , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo
6.
J Neuroinflammation ; 20(1): 134, 2023 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-37259140

RESUMO

BACKGROUND: Mutations in colony-stimulating factor 1 receptor (CSF1R) are known to cause adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), which has been recently demonstrated as a primary microgliopathy characterized by cognitive impairment. Although the molecular mechanism underlying CSF1R-mediated microgliopathy remains unclear, therapeutic strategies have generally targeted modulation of microglial function. In particular, the microglial inhibitor, minocycline, has been shown to attenuate learning and memory deficits in several neurodegenerative diseases. The objectives of this study were to investigate the pathogenic mechanisms underlying ALSP and to explore the therapeutic effects of minocycline in an in vivo model of ALSP. We hypothesized that inhibiting microglial activation via minocycline could reverse the behavior and pathological defects in ALSP model mice. METHODS: We generated a Csf1r haploinsufficiency mouse model of ALSP using CRISPR/Cas9 genome editing and conducted electrophysiological recordings of long-term potentiation (LTP) and behavioral tests to validate the recapitulation of clinical ALSP characteristics in 8- to 11-month-old mice. RNA-sequencing was used to explore enriched gene expression in the molecular pathogenesis of ALSP. Microglial activation was assessed by immunofluorescent detection of Iba1 and CD68 in brain sections of male ALSP mice and pro-inflammatory activation and phagocytosis were assessed in Csf1r+/- microglia. Therapeutic effects were assessed by behavioral tests, histological analysis, and morphological examination after four weeks of intraperitoneal injection with minocycline or vehicle control in Csf1r+/- mice and wild-type control littermates. RESULTS: We found that synaptic function was reduced in LTP recordings of neurons in the hippocampal CA1 region, while behavioral tests showed impaired spatial and cognitive memory specifically in male Csf1r+/- mice. Increased activation, pro-inflammatory cytokine production, and enhanced phagocytic capacity were also observed in Csf1r+/- microglia. Treatment with minocycline could suppress the activation of Csf1r+/- microglia both in vitro and in vivo. Notably, the behavioral and pathological deficits in Csf1r+/- mice were partially rescued by minocycline administration, potentially due to inhibition of microglial inflammation and phagocytosis in Csf1r+/- mice. CONCLUSIONS: Our study shows that CSF1R deficiency results in aberrant microglial activation, characterized by a pro-inflammatory phenotype and enhanced phagocytosis of myelin. Our results also indicate that microglial inhibition by minocycline can ameliorate behavioral impairment and ALSP pathogenesis in CSF1R-deficient male mice, suggesting a potential therapeutic target for CSF1R-related leukoencephalopathy. Collectively, these data support that minocycline confers protective effects against CSF1R-related microgliopathy in male ALSP model mice.


Assuntos
Leucoencefalopatias , Minociclina , Masculino , Animais , Camundongos , Minociclina/farmacologia , Minociclina/uso terapêutico , Neuroglia/metabolismo , Leucoencefalopatias/etiologia , Leucoencefalopatias/genética , Encéfalo/metabolismo , Microglia/metabolismo , Receptores de Fator Estimulador de Colônias/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo
7.
Brain Behav Immun ; 113: 275-288, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37482204

RESUMO

Over the past decade, compelling genetic evidence has highlighted the crucial role of microglial dysregulation in the development of Alzheimer's disease (AD). As resident immune cells in the brain, microglia undergo dystrophy and senescence during the chronic progression of AD. To explore the potential therapeutic benefits of replenishing the brain with new microglia in AD, we utilized the CSF1R inhibitor PLX3397 to deplete existing microglia and induce repopulation after inhibitor withdrawal in 5xFAD transgenic mice. Our findings revealed the remarkable benefits of microglial repopulation in ameliorating AD-associated cognitive deficits, accompanied by a notable elevation in synaptic proteins and an enhancement of hippocampal long-term potentiation (LTP). Additionally, we observed the profound restoration of microglial morphology and synaptic engulfment following their self-renewal. The impact of microglial repopulation on amyloid pathology is dependent on the duration of repopulation. Transcriptome analysis revealed a high resemblance between the gene expression profiles of repopulated microglia from 5xFAD mice and those of microglia from WT mice. Importantly, the dysregulated neurotrophic signaling pathway and hippocampal neurogenesis in the AD brain are restored following microglial replenishment. Lastly, we demonstrated that the repopulation restores the expression of brain-derived neurotrophic factor (BDNF) in microglia, thereby contributing to synaptic plasticity. In conclusion, our findings provide compelling evidence to support the notion that microglial self-renewal confers substantial benefits to the AD brain by restoring the BDNF neurotrophic signaling pathway. Thus, targeted microglial repopulation emerges as a highly promising and novel therapeutic strategy for alleviating cognitive impairment in AD.


Assuntos
Doença de Alzheimer , Camundongos , Animais , Doença de Alzheimer/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Microglia/metabolismo , Camundongos Transgênicos , Transdução de Sinais , Cognição , Modelos Animais de Doenças
8.
Zhonghua Nan Ke Xue ; 29(8): 705-710, 2023 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-38619516

RESUMO

Objective:The purpose of this study was to explore the causal relationship between nonalcoholic fatty liver disease (NAFLD) and the risk of erectile dysfunction (ED) by using two-sample Mendelian randomization (MR) analysis. METHODS: Single nucleotide polymorphisms (SNPs) were screened as instrumental variables (IVs) using the public genome-wide association study summary data set (GWAS). Univariate MR, bidirectional MR and multivariate MR methods were used to analyze the causal relationship between NAFLD and ED. RESULTS: IVW results showed that NAFLD was not associated with ED (OR=0.991 2, 95%CI: 0.955 2-1.0286, P=0.640 6). The results of reverse MR showed that there was no correlation between ED and NAFLD (OR=1.181 5, 95%CI: 0.820 8-1.7007, P=0.369 5). Multivariate MR results showed that there was still no causal relationship between the two diseases after adjusting for confounding factors. CONCLUSION: The results showed that there was no causal relationship between NAFLD and the risk of ED.


Assuntos
Disfunção Erétil , Hepatopatia Gordurosa não Alcoólica , Masculino , Humanos , Disfunção Erétil/epidemiologia , Disfunção Erétil/genética , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único
9.
Zhonghua Nan Ke Xue ; 29(2): 131-137, 2023 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-37847084

RESUMO

OBJECTIVE: To evaluate the effect of transurethral plasmakinetic enucleation of the prostate (PKEP) with complete preservation of the urethral mucosa in the 11-1 o'clock position on urinary continence and erectile function in BPH patients. METHODS: We retrospectively analyzed the clinical data on 84 cases of BPH treated by traditional PKEP (group A, n = 48) or modified PKEP with complete preservation of the urethral mucosa in the 11-1 o'clock position (group B, n = 36) from January 2017 to December 2021. All the patients had sexual activities within three months preoperatively. We followed up the patients for 12 months after surgery and compared the baseline, surgery-related and follow-up data between the two groups of patients. RESULTS: There were no statistically significant differences between the two groups of patients in age, disease duration, prostate volume, preoperative postvoid residual urine (PVR), preoperative maximum urinary flow rate (Qmax), IPSS, PSA level, QOL scores or IIEF-5 scores, nor in the operation time, intraoperative hemoglobin decrease, volume of resected tissue, bladder flushing time, postoperative hospital stay, or postoperative improvement of Qmax and IPSS. The rate of urinary continence was significantly higher in group B than in A at 1 month postoperatively (66.67% ï¼»24/36ï¼½ vs 43.25% ï¼»20/48ï¼½, P = 0.025) and so were IIEF-5 scores at 6 months (16.69 ± 3.21 vs 15.27 ± 2.74, P = 0.032) and 12 months (18.04 ± 2.04 vs 16.96 ± 2.54, P = 0.039), while the incidence rate of retrograde ejaculation markedly lower in the former than in the latter group at 6 months (33.33% ï¼»12/36ï¼½ vs 56.25% ï¼»28/48ï¼½, P = 0.018) and 12 months (25% ï¼»9/36ï¼½ vs 47.92% ï¼»23/48ï¼½, P = 0.027). At 1, 3, 6 and 12 months after surgery, the patients in group B also showed remarkably higher QOL scores than those in group B (2.61 ± 0.81 vs 2.12 ± 0.69, P = 0.005; 2.24 ± 0.66 vs 1.94 ± 0.51,P = 0.026; 2.12 ± 0.83 vs 1.80 ± 0.53,P = 0.047; and 1.94 ± 0.65 vs 1.72 ± 0.58, P = 0.038). CONCLUSION: Modified PKEP with complete preservation of the urethral mucosa in the 11-1 o'clock position can improve urinary continence, protect erectile function and ameliorate QOL in patients with BPH.


Assuntos
Disfunção Erétil , Hiperplasia Prostática , Ressecção Transuretral da Próstata , Masculino , Humanos , Hiperplasia Prostática/complicações , Hiperplasia Prostática/cirurgia , Disfunção Erétil/cirurgia , Qualidade de Vida , Estudos Retrospectivos , Mucosa , Resultado do Tratamento
10.
Angew Chem Int Ed Engl ; 62(11): e202216950, 2023 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-36625196

RESUMO

To conquer the bottleneck of sluggish kinetics in cathodic oxygen reduction reaction (ORR) of metal-air batteries, catalysts with dual-active centers have stood out. Here, a "pre-division metal clusters" strategy is firstly conceived to fabricate a N,S-dual doped honeycomb-like carbon matrix inlaid with CoN4 sites and wrapped Co2 P nanoclusters as dual-active centers (Co2 P/CoN4 @NSC-500). A crystalline {CoII 2 } coordination cluster divided by periphery second organic layers is well-designed to realize delocalized dispersion before calcination. The optimal Co2 P/CoN4 @NSC-500 executes excellent 4e- ORR activity surpassing the benchmark Pt/C. Theoretical calculation results reveal that the CoN4 sites and Co2 P nanoclusters can synergistically quicken the formation of *OOH on Co sites. The rechargeable Zn-air battery (ZAB) assembled by Co2 P/CoN4 @NSC-500 delivers ultralong cycling stability over 1742 hours (3484 cycles) under 5 mA cm-2 and can light up a 2.4 V LED bulb for ≈264 hours, evidencing the promising practical application potentials in portable devices.

11.
J Cell Mol Med ; 25(9): 4516-4521, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33783963

RESUMO

Both Colony-stimulating factor 1 receptor (CSF1R) and triggering receptor expressed on myeloid cells-2 (TREM2) are trans-membrane receptors and are expressed in the brain primarily by microglia. Mutations in these two microglia-expressed genes associated with neurodegenerative disease have recently been grouped under the term "microgliopathy". Several literatures have indicated that CSF1R and TREM2 encounters a stepwise shedding and TREM2 variants impair or accelerate the processing. However, whether CSF1R variant affects the shedding of CSF1R remains elusive. Here, plasmids containing human CSF1R or TREM2 were transiently transfected into the human embryonic kidney (HEK) 293T cells. Using Western Blot and/or ELISA assay, we demonstrated that, similar to those of TREM2, an N-terminal fragment (NTF) shedding of CSF1R ectodomain and a subsequent C-terminal fragment (CTF) of CSF1R intra-membrane were generated by a disintegrin and metalloprotease (ADAM) family member and by γ-secretase, respectively. And the shedding was inhibited by treatment with Batimastat, an ADAM inhibitor, or DAPT or compound E, a γ-secretase inhibitor. Importantly, we show that the cleaved fragments, both extracellular domain and intracellular domain of a common disease associated I794T variant, were decreased significantly. Together, our studies demonstrate a stepwise approach of human CSF1R cleavage and contribute to understand the pathogenicity of CSF1R I794T variant in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). These studies also suggest that the cleaved ectodomain fragment released from CSF1R may be proposed as a diagnostic biomarker for ALSP.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Leucoencefalopatias/patologia , Glicoproteínas de Membrana/metabolismo , Proteínas Mutantes/metabolismo , Mutação , Proteólise , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Receptores Imunológicos/metabolismo , Secretases da Proteína Precursora do Amiloide/genética , Células HEK293 , Humanos , Leucoencefalopatias/genética , Leucoencefalopatias/metabolismo , Glicoproteínas de Membrana/genética , Proteínas Mutantes/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptores Imunológicos/genética
12.
J Am Chem Soc ; 143(8): 3256-3263, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33600160

RESUMO

Desaturation of unactivated alkanes remains a challenging yet desirable strategy to make olefins. The Illicium sesquiterpenes usually possess highly oxygenated cage-like architectures, and some of them exhibit prominent neurotrophic effects. Here, we disclose a unique photochemical desaturation strategy for the efficient, highly stereocontrolled total syntheses of five Illicium sesquiterpenes from inexpensive (R)-pulegone, featuring a 13-step gram-scale synthesis of (-)-merrilactone A. The efficiency of the syntheses derives from an expedient construction of a tetracyclic framework via two annulations, a site-specific photoinduced single-step desaturation in a complex hydrocarbon system, and diverse oxygenation manipulations around the resultant olefin intermediate. This work highlights how late-stage desaturation can dramatically streamline the synthesis of complex terpenes and diverse non-natural analogues for establishing the structure-activity relationship and elucidating their molecular mechanisms of bioactivity.


Assuntos
Illicium/química , Processos Fotoquímicos , Sesquiterpenos/química , Sesquiterpenos/síntese química , Técnicas de Química Sintética , Custos e Análise de Custo , Cinética , Oxigênio/química
13.
J Neuroinflammation ; 18(1): 286, 2021 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-34893068

RESUMO

BACKGROUND: TREM2 is a microglial receptor genetically linked to the risk for Alzheimer's disease (AD). The cerebrospinal fluid (CSF) levels of soluble TREM2 (sTREM2) have emerged as a valuable biomarker for the disease progression in AD and higher CSF levels of sTREM2 are linked to slower cognitive decline. Increasing sTREM2 in mouse models of amyloidosis reduces amyloid-related pathology through modulating microglial functions, suggesting a beneficial role of sTREM2 in microglia biology and AD pathology. METHODS: In the current study, we performed serial C- and N-terminal truncations of sTREM2 protein to define the minimal sequence requirement for sTREM2 function. We initially assessed the impacts of sTREM2 mutants on microglial functions by measuring cell viability and inflammatory responses. The binding of the sTREM2 mutants to oligomeric Aß was determined by solid-phase protein binding assay and dot blot assay. We further evaluated the impacts of sTREM2 mutants on amyloid-related pathology by direct stereotaxic injection of sTREM2 proteins into the brain of 5xFAD mice. RESULTS: We found that both sTREM2 fragments 41-81 and 51-81 enhance cell viability and inflammatory responses in primary microglia. However, the fragment 51-81 exhibited impaired affinity to oligomeric Aß. When administrated to the 5xFAD mice brain, the sTREM2 fragment 41-81, but not 51-81, increased the number of plaque-associated microglia and reduced the plaque deposition. Interestingly, the fragment 41-81 was more efficient than the physiological form of sTREM2 in ameliorating Aß-related pathology. CONCLUSIONS: Our results indicate that the interaction of sTREM2 truncated variants with Aß is essential for enhancing microglial recruitment to the vicinity of an amyloid plaque and reducing the plaque load. Importantly, we identified a 41-amino acid sequence of sTREM2 that is sufficient for modulating microglial functions and more potent than the full-length sTREM2 in reducing the plaque load and the plaque-associated neurotoxicity. Taken together, our data provide more insights into the mechanisms underlying sTREM2 function and the minimal active sTREM2 sequence represents a promising candidate for AD therapy.


Assuntos
Amiloidose/genética , Amiloidose/patologia , Encéfalo/patologia , Glicoproteínas de Membrana/genética , Microglia/patologia , Fenótipo , Receptores Imunológicos/genética , Sequência de Aminoácidos , Animais , Células Cultivadas , Células HEK293 , Humanos , Camundongos
14.
FASEB J ; 34(8): 10984-10997, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32613609

RESUMO

Mutation of Triggering receptor expressed on myeloid cells 2 (TREM2) impairs the response of microglia to amyloid-ß (Aß) pathology in Alzheimer's disease (AD), although the mechanism governing TREM2-regulated microglia recruitment to Aß plaques remains unresolved. Here, we confirm that TREM2 mutation attenuates microglial migration. Then, using Trem2-/- mice and an R47H variant mouse model for AD generated for this study, we show that TREM2 deficiency or the AD-associated R47H mutation results in inhibition of FAK and Rac1/Cdc42-GTPase signaling critical for cell migration. Intriguingly, treatment with CN04, a Rac1/Cdc42-GTPase activator, partially enhances microglial migration in response to oligomeric Aß42 in Trem2-/- or R47H microglia both in vitro and in vivo. Our study shows that the dysfunction of microglial migration in the AD-associated TREM2 R47H variant is caused by FAK/Rac1/Cdc42 signaling disruption, and that activation of this signaling ameliorates impaired microglial migration response to Aß42 , suggesting a therapeutic target for R47H-bearing patients with high risk of AD.


Assuntos
Peptídeos beta-Amiloides/genética , Movimento Celular/genética , Quinase 1 de Adesão Focal/genética , GTP Fosfo-Hidrolases/genética , Microglia/patologia , Células Mieloides/metabolismo , Neuropeptídeos/genética , Fragmentos de Peptídeos/genética , Proteína cdc42 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/genética , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Encéfalo/patologia , Células Cultivadas , Modelos Animais de Doenças , Mutação com Perda de Função/genética , Masculino , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/metabolismo , Células Mieloides/patologia , Transdução de Sinais/genética
15.
Inorg Chem ; 60(5): 2899-2904, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33591171

RESUMO

Layering AgNO3 in alcohol onto octavinylsilsesquioxane (OVS) in CHCl3 results in a one-dimensional coordination polymer, {Ag4(NO3)4(OVS)·solvents}n (SD/Ag4a-d), consisting of unprecedented flat weakly bonded Ag4(NO3)4 alternating with the firmly covalent OVS through AgI-πC═C bonds. The preferential assembling medium for SD/Ag4a is proven to be alcohols, where a 4:1 silver-OVS adduct is detected by electrospray ionization mass spectrometry. The present outcomes may assist our knowledge of particular interactions for supramolecular architectures of a polynuclear silver system built from OVS containing eight pendent olefin tails.

16.
Inorg Chem ; 60(2): 671-681, 2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33395274

RESUMO

Luminescent metal-organic frameworks (LMOFs) as sensors showing highly efficient detection toward toxic heavy-metal ions are in high demand for human health and environmental protection. A novel nanocage-based N-rich LMOF (LCU-103) has been constructed and characterized. It is a 2-fold interpenetrating structure built from N-rich {Zn6(dttz)4} nanocages extended by N-donor ligand Hdpa [H3dttz = 4,5-di(1H-tetrazol-5-yl)-2H-1,2,3-triazole; Hdpa = 4,4'-dipyridylamine]. Notably, LCU-103 contains abundant N functional sites anchoring on both the windows of nanocages and the inner channels of the framework that can interact with metal ions and then recognize them. As a result, it can serve as a luminescent sensing material for detecting trace amounts of Fe3+ and Cu2+ ions with low limits of detection (LODs) of 1.45 and 1.66 µM, respectively, through a luminescent quenching mechanism. Meanwhile, LCU-103 as a LMOF sensor exhibits several advantages such as high sensitivity, appropriate selectivity (for Fe3+ in H2O), recycling stability, and fast response times in N,N-dimethylformamide. Moreover, LCU-103 also displays good luminescent quenching activity toward Fe3+ in H2O and a simulated 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid biological system with low LODs of 1.51 and 1.52 µM, respectively. LCU-103 test papers were further prepared to offer easy and real-time detection of Fe3+ and Cu2+ ions. Importantly, when density functional theory calculations and multiple experimental evidence, including X-ray photoelectron spectroscopy, UV-vis absorption, luminescence decay lifetimes, and quantum efficiencies, are combined, a preferred N-donor site and possible weak interaction sensing mechanism is also proposed to elucidate the quenching effect.

17.
Nanotechnology ; 32(15): 155704, 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33373982

RESUMO

The magnetotransport properties of a hybrid InSe/monolayer graphene in a SiC system are systematically studied. Compared to those of its bare graphene counterpart, in InSe/graphene, we can effectively modify the carrier density, mobility, effective mass, and electron-electron (e-e) interactions enhanced by weak disorder. We show that in bare graphene and hybrid InSe/graphene systems, the logarithmic temperature (lnT) dependence of the Hall slope R H = Î´R xy /δB = Î´ρ xy /δB can be used to probe e-e interaction effects at various temperatures even when the measured resistivity does not show a lnT dependence due to strong electron-phonon scattering. Nevertheless, one needs to be certain that the change of R H is not caused by an increase of the carrier density by checking the magnetic field position of the longitudinal resistivity minimum at different temperatures. Given the current challenges in gating graphene on SiC with a suitable dielectric layer, our results suggest that capping a van der Waals material on graphene is an effective way to modify the electronic properties of monolayer graphene on SiC.

18.
Inorg Chem ; 59(5): 2680-2688, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32077693

RESUMO

Six novel copper(I) cluster-based coordination polymers (CPs) [Cu9(pzt)7Cl2]n (1), [Cu2(pzt)Cl]n (2), [Cu4(pzt)3Br]n (3), [Cu(pzt)]n (4), [Cu4(pzt)3I]n (5), and [Cu7(pzt)6I]n (6) were solvothermally synthesized using Hpzt (Hpzt = pyrazine-2-thiol) ligand and well-characterized by elemental analysis, infrared (IR) spectroscopy, powder X-ray diffraction (PXRD), and single-crystal X-ray diffraction (SCXRD). Six CPs exhibit either 2D (4 and 6) or 3D (1-3, and 5) network based on diverse multinuclear {CuxSy} clusters. The structural evolutions of 1-6 are greatly influenced by types of metal halides and the ligand-to-metal molar ratio used in the reaction. Among them, compound 1 displays interesting temperature-dependent photoluminescence arising from triplet cluster-centered (3CC) excited state from the cluster metal core. Compounds 1-6 also exhibit photocurrent responses upon visible-light illumination (λ = 420 nm) in the order 6 > 5 > 3 > 1 > 4 > 2. This work not only shows the structural diversity of {CuxSy} clusters-based CPs but also provides an interesting insight into structural modulation using crystal engineering concept.

19.
Compr Psychiatry ; 97: 152159, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31931428

RESUMO

BACKGROUND: Depression is associated with inflammation and Alzheimer's disease (AD). However, detailed molecular mechanisms linking mood, neuroinflammation and AD remain unclear. Although changes in peripheral inflammatory factors such as Interleukin 18 (IL18), and AD-associated amyloid-ß (Aß) peptides have been linked to depression, a solid relationship between these factors in depressive disorder has yet to be established. This study aims to further determine whether plasma IL18, Aß40, Aß42, and the AD-associated tangle component Tau, as well as IL18 single nucleotide polymorphisms (SNPs) may be biomarkers for depression. METHODS: We measured plasma IL18, Aß40, Aß42, and Tau in 64 depressive patients and 75 healthy controls, and characterized genotypes of three IL18 SNPs (rs187238, rs1946518 and rs1946519) in these subjects. Comparisons between depressive patients and controls were carried out in males, in females or in combination. Regression analyses were conducted to examine the correlation between these parameters. RESULTS: We found that none of the plasma levels of IL18, Aß40, Aß42, and Tau, the ratio of Aß42/Aß40, and the genotypes of IL18 SNPs were significantly different between combined depressive patients and combined healthy controls, or between male depressive patients and male controls. However, IL18 levels were less in females than in males in healthy people and were significantly increased in female depressive patients compared to female controls. Moreover, IL18 and standardized IL18 were correlated with standardized Aß42/Aß40 ratio and standardized Tau in depressive patients. CONCLUSIONS: Plasma IL18 may be a potential biomarker for depression in women.


Assuntos
Peptídeos beta-Amiloides/sangue , Depressão/sangue , Interleucina-18/sangue , Proteínas tau/sangue , Idoso , Apolipoproteínas E , Biomarcadores/sangue , Estudos de Casos e Controles , Depressão/diagnóstico , Depressão/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/sangue , Polimorfismo de Nucleotídeo Único
20.
Neuroimmunomodulation ; 26(2): 67-76, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30928987

RESUMO

OBJECTIVE(S): Neuroinflammation is an important contributor to the development of seizures and epilepsy. Micro-RNA-155 (miR-155) plays a critical role in immunity and -inflammation. This study aims to explore the function of miR-155 and miR-155-mediated inflammation in epilepsy. METHODS: About 8-week-old male C57BL/6 mice were administered an intraperitoneal injection (i.p.) of kainic acid (KA) (15 mg/kg) or saline. The mice in the KA group developing acute seizure were further subjected to intracerebroventricular injection (i.c.v.) of antagomir negative control (NC) or miR-155 antagomir. Animal behavior was observed according to Racine's scale, and electroencephalographs were recorded. Primary microglia were cultured and treated with antagomir NC or antagomir. Whole-cell electrophysiological recording was conducted to detect the spontaneous EPSCs and IPSCs in the neurons treated with different conditioned medium from those microglia. miR-155 were detected by qRT-PCR in those models, as well as in the brain or blood from epileptic patients and healthy controls. RESULTS: miR-155 was abundantly expressed in glial cells compared with neurons, and its expression was markedly elevated in the brain of epilepsy patients and KA-induced seizure mice. Silencing miR-155 attenuated KA-induced seizure, abnormal electroencephalography, proinflammatory cytokine expression, and microglia morphology change. Moreover, conditioned media from KA-treated microglia impaired neuron excitability, whereas conditioned media from KA and miR-155 antagomir co-treated microglia had no such effects. Finally, miR-155 levels were significantly higher in the blood of epilepsy patients than those of healthy controls. CONCLUSION(S): These findings demonstrate that aberrant upregulation of miR-155 contributes to epileptogenesis through inducing microglia neuroinflammation.


Assuntos
Epilepsia do Lobo Temporal/metabolismo , MicroRNAs/metabolismo , Microglia/metabolismo , Convulsões/metabolismo , Adulto , Animais , Convulsivantes/toxicidade , Epilepsia do Lobo Temporal/imunologia , Feminino , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Ácido Caínico/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/imunologia , Microglia/imunologia , Convulsões/induzido quimicamente , Convulsões/imunologia
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