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Genetic studies have highlighted microglia as pivotal in orchestrating Alzheimer's disease (AD). Microglia that adhere to Aß plaques acquire a transcriptional signature, "disease-associated microglia" (DAM), which largely emanates from the TREM2-DAP12 receptor complex that transmits intracellular signals through the protein tyrosine kinase SYK. The human TREM2R47H variant associated with high AD risk fails to activate microglia via SYK. We found that SYK-deficient microglia cannot encase Aß plaques, accelerating brain pathology and behavioral deficits. SYK deficiency impaired the PI3K-AKT-GSK-3ß-mTOR pathway, incapacitating anabolic support required for attaining the DAM profile. However, SYK-deficient microglia proliferated and advanced to an Apoe-expressing prodromal stage of DAM; this pathway relied on the adapter DAP10, which also binds TREM2. Thus, microglial responses to Aß involve non-redundant SYK- and DAP10-pathways. Systemic administration of an antibody against CLEC7A, a receptor that directly activates SYK, rescued microglia activation in mice expressing the TREM2R47H allele, unveiling new options for AD immunotherapy.
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Doença de Alzheimer , Microglia , Animais , Camundongos , Humanos , Microglia/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/patologia , Placa Amiloide/metabolismo , Encéfalo/metabolismo , Modelos Animais de Doenças , Quinase Syk/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Receptores Imunológicos/metabolismoRESUMO
The TREM2-DAP12 receptor complex sustains microglia functions. Heterozygous hypofunctional TREM2 variants impair microglia, accelerating late-onset Alzheimer's disease. Homozygous inactivating variants of TREM2 or TYROBP-encoding DAP12 cause Nasu-Hakola disease (NHD), an early-onset dementia characterized by cerebral atrophy, myelin loss and gliosis. Mechanisms underpinning NHD are unknown. Here, single-nucleus RNA-sequencing analysis of brain specimens from DAP12-deficient NHD individuals revealed a unique microglia signature indicating heightened RUNX1, STAT3 and transforming growth factor-ß signaling pathways that mediate repair responses to injuries. This profile correlated with a wound healing signature in astrocytes and impaired myelination in oligodendrocytes, while pericyte profiles indicated vascular abnormalities. Conversely, single-nuclei signatures in mice lacking DAP12 signaling reflected very mild microglial defects that did not recapitulate NHD. We envision that DAP12 signaling in microglia attenuates wound healing pathways that, if left unchecked, interfere with microglial physiological functions, causing pathology in human. The identification of a dysregulated NHD microglia signature sparks potential therapeutic strategies aimed at resetting microglia signaling pathways.
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Demência , Panencefalite Esclerosante Subaguda , Animais , Humanos , Camundongos , Encéfalo/metabolismo , Demência/metabolismo , Demência/patologia , Glicoproteínas de Membrana/metabolismo , Microglia/metabolismo , Receptores Imunológicos/metabolismo , Panencefalite Esclerosante Subaguda/metabolismo , Panencefalite Esclerosante Subaguda/patologiaRESUMO
Elevated risk of developing Alzheimer's disease (AD) is associated with hypomorphic variants of TREM2, a surface receptor required for microglial responses to neurodegeneration, including proliferation, survival, clustering, and phagocytosis. How TREM2 promotes such diverse responses is unknown. Here, we find that microglia in AD patients carrying TREM2 risk variants and TREM2-deficient mice with AD-like pathology have abundant autophagic vesicles, as do TREM2-deficient macrophages under growth-factor limitation or endoplasmic reticulum (ER) stress. Combined metabolomics and RNA sequencing (RNA-seq) linked this anomalous autophagy to defective mammalian target of rapamycin (mTOR) signaling, which affects ATP levels and biosynthetic pathways. Metabolic derailment and autophagy were offset in vitro through Dectin-1, a receptor that elicits TREM2-like intracellular signals, and cyclocreatine, a creatine analog that can supply ATP. Dietary cyclocreatine tempered autophagy, restored microglial clustering around plaques, and decreased plaque-adjacent neuronal dystrophy in TREM2-deficient mice with amyloid-ß pathology. Thus, TREM2 enables microglial responses during AD by sustaining cellular energetic and biosynthetic metabolism.
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Doença de Alzheimer/patologia , Metabolismo Energético , Glicoproteínas de Membrana/metabolismo , Microglia/metabolismo , Receptores Imunológicos/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Doença de Alzheimer/metabolismo , Animais , Autofagia , Creatinina/análogos & derivados , Creatinina/metabolismo , Modelos Animais de Doenças , Humanos , Lectinas Tipo C/metabolismo , Macrófagos/metabolismo , Glicoproteínas de Membrana/genética , Camundongos , Microglia/patologia , Neuritos/metabolismo , Placa Amiloide/metabolismo , Receptores Imunológicos/genética , Serina-Treonina Quinases TOR/metabolismoRESUMO
Microglia are parenchymal macrophages of the CNS; as professional phagocytes they are important for maintenance of the brain's physiology. These cells are generated through primitive hematopoiesis in the yolk sac and migrate into the brain rudiment after establishment of embryonic circulation. Thereafter, microglia develop in a stepwise fashion, reaching complete maturity after birth. In the CNS, microglia self-renew without input from blood monocytes. Recent RNA-sequencing studies have defined a molecular signature for microglia under homeostasis. However, during disease, microglia undergo remarkable phenotypic changes, which reflect the acquisition of specialized functions tailored to the pathological context. In addition to microglia, the brain-border regions host populations of extraparenchymal macrophages with disparate origins and phenotypes that have recently been delineated. In this review we outline recent findings that provide a deeper understanding of both parenchymal microglia and extraparenchymal brain macrophages in homeostasis and during disease.
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Encéfalo/citologia , Encéfalo/imunologia , Macrófagos , Microglia , Animais , Linhagem da Célula , Homeostase/imunologia , Humanos , Macrófagos/citologia , Macrófagos/imunologia , Microglia/citologia , Microglia/imunologiaRESUMO
This paper proposes a steered response power (SRP) approach with trade-off prewhitening to acoustic source localization. To obtain effective compromise prefiltering of microphone signals, the sparsity of speech amplitude spectrum is used to establish a convex-constraint linear prediction model, which is solved by a split Bregman method. The presented approach unifies the traditional SRP and steered response power via phase transform prefiltering methods and achieves a good compromise between them from the perspective of localization performance. The superiority of the proposed method is demonstrated in noisy and reverberant environments.
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In wastewater-based epidemiology (WBE), the selection of appropriate biomarkers presents a significant challenge. Recently, sulfated bisphenols have garnered attention as potential WBE biomarkers due to their increased stability in wastewater compared to glucuronide conjugates. This study aims to comprehensively assess the feasibility of employing sulfated BPA and BPS as WBE biomarkers by analyzing both WBE and human biomonitoring data. To conduct this research, wastewater samples were collected from six domestic wastewater treatment plants in Guangzhou, China, and urinary concentration of BPA and BPS were obtained from peer-reviewed literature. The results revealed that mean urinary concentrations of BPA and BPS, calculated using Monte Carlo simulations, significantly exceeded those reported in human biomonitoring studies. Furthermore, the per capita mass load ratio of sulfated BPA and BPS in human urine to the mass load in wastewater was found to be below 10 %. This outcome suggests that the excretion of BPA-S and BPS-S in urine does not make a substantial contribution to wastewater, hinting at the existence of other notable sources. Consequently, our study concludes that sulfated BPA-S and BPS-S are not suitable candidates as WBE biomarkers. This work provides a referenceable analytical framework for evaluating the feasibility of WBE biomarkers and emphasizes the necessity for caution when utilizing WBE to assess human exposure to chemicals.
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Compostos Benzidrílicos , Biomarcadores , Fenóis , Sulfonas , Águas Residuárias , Poluentes Químicos da Água , Humanos , Fenóis/urina , Águas Residuárias/química , Compostos Benzidrílicos/urina , China , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/urina , Biomarcadores/urina , Estudos de Viabilidade , Sulfatos/urina , Sulfatos/análise , Monitoramento Ambiental/métodos , Vigilância Epidemiológica Baseada em Águas ResiduáriasRESUMO
The mechanism by which brown adipose tissue (BAT) regulates bone metabolism is unclear. Here, we reveal that BAT secretes S100A8/A9, a previously unidentified BAT adipokine (batokine), to impair bone formation. Brown adipocytes-specific knockout of Rheb (RhebBAD KO), the upstream activator of mTOR, causes BAT malfunction to inhibit osteogenesis. Rheb depletion induces NF-κB dependent S100A8/A9 secretion from brown adipocytes, but not from macrophages. In wild-type mice, age-related Rheb downregulation in BAT is associated with enhanced S100A8/A9 secretion. Either batokines from RhebBAD KO mice, or recombinant S100A8/A9, inhibits osteoblast differentiation of mesenchymal stem cells in vitro by targeting toll-like receptor 4 on their surfaces. Conversely, S100A8/A9 neutralization not only rescues the osteogenesis repressed in the RhebBAD KO mice, but also alleviates age-related osteoporosis in wild-type mice. Collectively, our data revealed an unexpected BAT-bone crosstalk driven by Rheb-S100A8/A9, uncovering S100A8/A9 as a promising target for the treatment, and potentially, prevention of osteoporosis.
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Microglia help limit the progression of Alzheimer's disease (AD) by constraining amyloid-ß (Aß) pathology, effected through a balance of activating and inhibitory intracellular signals delivered by distinct cell surface receptors. Human leukocyte Ig-like receptor B4 (LILRB4) is an inhibitory receptor of the immunoglobulin (Ig) superfamily that is expressed on myeloid cells and recognizes apolipoprotein E (ApoE) among other ligands. Here, we find that LILRB4 is highly expressed in the microglia of patients with AD. Using mice that accumulate Aß and carry a transgene encompassing a portion of the LILR region that includes LILRB4, we corroborated abundant LILRB4 expression in microglia wrapping around Aß plaques. Systemic treatment of these mice with an anti-human LILRB4 monoclonal antibody (mAb) reduced Aß load, mitigated some Aß-related behavioral abnormalities, enhanced microglia activity, and attenuated expression of interferon-induced genes. In vitro binding experiments established that human LILRB4 binds both human and mouse ApoE and that anti-human LILRB4 mAb blocks such interaction. In silico modeling, biochemical, and mutagenesis analyses identified a loop between the two extracellular Ig domains of LILRB4 required for interaction with mouse ApoE and further indicated that anti-LILRB4 mAb may block LILRB4-mApoE by directly binding this loop. Thus, targeting LILRB4 may be a potential therapeutic avenue for AD.
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Doença de Alzheimer , Microglia , Humanos , Camundongos , Animais , Microglia/metabolismo , Anticorpos/metabolismo , Receptores de Superfície Celular/metabolismo , Amiloide/metabolismo , Modelos Animais de Doenças , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Apolipoproteínas E , Leucócitos/metabolismo , Camundongos Transgênicos , Glicoproteínas de Membrana/metabolismo , Receptores Imunológicos/metabolismoRESUMO
Substantial amounts of extracellular polymeric substances (EPS) are present in sludge from wastewater treatment plants (WWTP), and EPS can significantly affect the fate, bioavailability, and toxicity of microplastics (MPs) that coexist in the effluent, however, the mechanism of action between EPS and microplastics remains unclear. In addition, ultraviolet (UV) disinfection is indispensable in the wastewater treatment process in WWTP, which can significantly affect the characteristics of EPS. Therefore, it is of great significance to study the photochemical characteristics of EPS and the effect on binding MPs. In this study, using multispectral technology and two-dimensional correlation spectroscopy analysis, indicates that the molecular weight and aromaticity of EPS after phototransformation were reduced. The results showed that the adsorption of EPS on PSMPs was in the order of TB-EPS > LB-EPS > S-EPS, which was positively correlated with the SUVA254, but negatively correlated with O/C of EPS. This indicates that the main adsorption mechanisms of PSMPs on EPS were π-π and hydrophobicity. The adsorption capacity of S-EPS, LB-EPS and TB-EPS to PSMPs decreased with the increasing of illumination time. After phototransformation, the adsorption sensitivity and reaction sequence of EPS and PSMPs did not change much. This research provides a theoretical basis for understanding the photochemical transformation of extracellular polymers and the morphology and migration of microplastics in sewage treatment, and evaluating the impact of microplastics on ecosystems.
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Heavy metal cations are a typical type of inorganic pollutant that has persistent distribution characteristics in aquatic environments and are easily adsorbed on carriers, posing serious threats to ecological safety and human health. Some studies have shown that the coexistence of dissolved organic matter (DOM) and microplastics (MPs) promotes the adsorption of heavy metal cations, but the mechanism of promoting the adsorption process has not been thoroughly studied. In this study, the effect of polystyrene microplastics (PSMPs) on the binding properties of Pb2+ onto humic acid (HA) in aquatic environments was investigated by spectral analysis and two-dimensional correlation (2D-COS) analysis. When PSMPs co-existed with HA, the adsorption capacity of Pb2+ increased. On the one hand, Pb2+ is directly adsorbed on HA through the mechanism of complexation reaction, ion exchange and electrostatic interaction. On the other hand, Pb2+ is first adsorbed on PSMPs by electrostatic action and indirectly adsorbed on HA in the form of PSMPs-Pb2+ owing to the interaction between HA and PSMPs, which increases the adsorption amount of Pb2+ on HA. This study is significant for studying the migration and regression of heavy metal cation contaminants when PSMPs co-exist with DOM in an aqueous environment.
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Bisphenol analogues (BPs) are ubiquitous in the environment and have gained significant attention regarding their associated health risks. However, there is a lack of comprehensive biomonitoring data on BPs and their metabolites in human urine. To address this, we conducted a study evaluate the exposure to BPs in the general population of Guangzhou, China. A total of 1440 urine samples were collected from volunteers and analyzed for the presence of BPs and their metabolites after being pooled into 36 groups based on age and gender. The findings revealed the common detection of ten free-form BPs, as well as the urinary metabolites of BPA and BPS, in the pooled urine samples. BPA was the predominant free-form compound, constituting 50% of the total BPs. The primary urinary metabolites of BPA and BPS are BPA-G and BPS-G, respectively, indicating glucuronidation as their primary metabolic pathway. The composition of urinary metabolites of BPA and BPS varied by age and sex, while the concentration of total BPs in urine was not significantly associated with age and sex. Enzymatic hydrolysis yielded a mean amplification of individual BPs concentrations in urine samples ranging from 1.8 times (BPA) to 4.6 times (BPS). Based on the outcomes, it was estimated that conjugated forms accounted for 96.9%, 96.2%, 94.7%, 94.1%, 92.6%, 89.1%, 87.3%, 87.2%, 87.1% and 85.8% of BPP, BPAF, BPZ, BPE, BPAP, BPF, BPA, BPC, BPS and BPF, respectively, in the pooled urine samples. Preliminary risk assessments indicated that the estimated daily intake of BPA was much higher than the latest proposed tolerable daily intake. Due to the unavailability of health-based guideline values for alternative BPs, some of them exhibit daily intakes comparable to BPA, implying that greater attention should be paid to health risks associated with exposure to BPs.
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Monitoramento Biológico , Fenóis , Humanos , Fenóis/análise , Compostos Benzidrílicos/análise , ChinaRESUMO
Demyelination is a hallmark of multiple sclerosis, leukoencephalopathies, cerebral vasculopathies, and several neurodegenerative diseases. The cuprizone mouse model is widely used to simulate demyelination and remyelination occurring in these diseases. Here, we present a high-resolution single-nucleus RNA sequencing (snRNA-seq) analysis of gene expression changes across all brain cells in this model. We define demyelination-associated oligodendrocytes (DOLs) and remyelination-associated MAFBhi microglia, as well as astrocytes and vascular cells with signatures of altered metabolism, oxidative stress, and interferon response. Furthermore, snRNA-seq provides insights into how brain cell types connect and interact, defining complex circuitries that impact demyelination and remyelination. As an explicative example, perturbation of microglia caused by TREM2 deficiency indirectly impairs the induction of DOLs. Altogether, this study provides a rich resource for future studies investigating mechanisms underlying demyelinating diseases.
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Doenças Desmielinizantes , Remielinização , Animais , Camundongos , Doenças Desmielinizantes/metabolismo , Transcriptoma/genética , Encéfalo/metabolismo , Oligodendroglia/metabolismo , Microglia/metabolismo , Cuprizona/toxicidade , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Bainha de Mielina/metabolismoRESUMO
Human exposure to bisphenol A (BPA) and bisphenol S (BPS) has garnered considerable global health concerns. In this paper, the daily intake (DI) of BPA and BPS in the general population of Guangzhou, China, were back-calculated using the biomarkers BPA glucuronides (BPA-G) and BPS glucuronides (BPS-G), respectively. The biomarkers are preferable to total BPA and BPS measurements because they are not susceptible to external contamination. A total of 1440 urine samples were gathered from the general population in Guangzhou, China, which were classified by age and sex into 36 pooled urine samples. 100% and 98% of pooled urine samples contained BPA-G and BPS-G at median values of 1.57 and 0.38 ng/mL, respectively. Based on urinary BPA-G and BPS-G concentrations, we determined the median DI of BPA and BPS to be 31.07 and 7.37 ng/(kg bw*d), respectively, and the highest values to be 106.77 ng/(kg bw*d) and 18.19 ng/(kg bw*d), respectively. Furthermore, our results showed that for the entire dataset, the DI of BPA and BPS were considerably greater in males than in females (p < 0.01)and declined significantly with age (p < 0.05). For risk assessment, the estimated DIs of BPA and BPS were much lower than the European Food Safety Authority' s (EFSA) the temporary acceptable reference dose of 4 µg/(kg bw*d) advised for BPA, suggesting that the exposure risk of BPA and BPS for Guangzhou population is within a controllable safety range. This is the first study to investigate BPA and BPS exposure in the general population of Guangzhou, China, on the basis of urinary metabolites.
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Compostos Benzidrílicos , Sulfonas , Masculino , Feminino , Humanos , Compostos Benzidrílicos/análise , China , Medição de RiscoRESUMO
Sepsis is a leading cause of death in critical illness, and its pathophysiology varies depending on preexisting medical conditions. Here we identified nonalcoholic fatty liver disease (NAFLD) as an independent risk factor for sepsis in a large clinical cohort and showed a link between mortality in NAFLD-associated sepsis and hepatic mitochondrial and energetic metabolism dysfunction. Using in vivo and in vitro models of liver lipid overload, we discovered a metabolic coordination between hepatocyte mitochondria and liver macrophages that express triggering receptor expressed on myeloid cells-2 (TREM2). Trem2-deficient macrophages released exosomes that impaired hepatocytic mitochondrial structure and energy supply because of their high content of miR-106b-5p, which blocks Mitofusin 2 (Mfn2). In a mouse model of NAFLD-associated sepsis, TREM2 deficiency accelerated the initial progression of NAFLD and subsequent susceptibility to sepsis. Conversely, overexpression of TREM2 in liver macrophages improved hepatic energy supply and sepsis outcome. This study demonstrates that NAFLD is a risk factor for sepsis, providing a basis for precision treatment, and identifies hepatocyte-macrophage metabolic coordination and TREM2 as potential targets for future clinical trials.
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Comunicação Celular , Hepatócitos/metabolismo , Macrófagos/metabolismo , Glicoproteínas de Membrana/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores Imunológicos/metabolismo , Sepse/metabolismo , Animais , Metabolismo Energético/genética , Feminino , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Hepatócitos/patologia , Humanos , Macrófagos/patologia , Masculino , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Knockout , MicroRNAs/genética , MicroRNAs/metabolismo , Mitocôndrias Hepáticas/genética , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Hepáticas/patologia , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Receptores Imunológicos/genética , Sepse/genética , Sepse/patologiaRESUMO
Senescent cells contribute to pathology and dysfunction in animal models1. Their sparse distribution and heterogenous phenotype have presented challenges for detecting them in human tissues. We developed a senescence eigengene approach to identify these rare cells within large, diverse populations of postmortem human brain cells. Eigengenes are useful when no single gene reliably captures a phenotype, like senescence; they also help to reduce noise, which is important in large transcriptomic datasets where subtle signals from low-expressing genes can be lost. Each of our eigengenes detected ~2% senescent cells from a population of ~140,000 single nuclei derived from 76 postmortem human brains with various levels of Alzheimer's disease (AD) pathology. More than 97% of the senescent cells were excitatory neurons and overlapped with tau-containing neurofibrillary tangles (NFTs). Cyclin dependent kinase inhibitor 2D (CDKN2D/p19) was predicted as the most significant contributor to the primary senescence eigengene. RNAscope and immunofluorescence confirmed its elevated expression in AD brain tissue whereby p19-expressing neurons had 1.8-fold larger nuclei and significantly more cells with lipofuscin than p19-negative neurons. These hallmark senescence phenotypes were further elevated in the presence of NFTs. Collectively, CDKN2D/p19-expressing neurons with NFTs represent a unique cellular population in human AD with a senescence phenotype. The eigengenes developed may be useful in future senescence profiling studies as they accurately identified senescent cells in snRNASeq datasets and predicted biomarkers for histological investigation.
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Doença de Alzheimer , Neurônios , Animais , Humanos , Inibidor de Quinase Dependente de Ciclina p19/metabolismo , Doença de Alzheimer/genética , Senescência Celular/genética , Encéfalo/metabolismoRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Glia have been implicated in Alzheimer's disease (AD) pathogenesis. Variants of the microglia receptor triggering receptor expressed on myeloid cells 2 (TREM2) increase AD risk, and activation of disease-associated microglia (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene-expression changes associated with AD pathology and TREM2 in 5XFAD mice and in human AD by single-nucleus RNA sequencing. We confirmed the presence of Trem2-dependent DAM and identified a previously undiscovered Serpina3n+C4b+ reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral-nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less evident in TREM2-R47H and TREM2-R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences.
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Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Glicoproteínas de Membrana/metabolismo , Receptores Imunológicos/metabolismo , Transcriptoma/genética , Idoso , Peptídeos beta-Amiloides/metabolismo , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Axônios/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/metabolismo , Microglia/patologia , Pessoa de Meia-Idade , Degeneração Neural/patologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Transcrição GênicaRESUMO
Alzheimer's disease (AD) is a late-onset dementia characterized by the deposition of amyloid plaques and formation of neurofibrillary tangles (NFTs) which lead to neuronal loss and cognitive deficits. Abnormal protein aggregates in the AD brain are also associated with reactive microglia and astrocytes. Whether this glial response is beneficial or detrimental in AD pathology is under debate. Microglia are the resident innate immune cells in the central nervous system (CNS) that survey the surrounding environment. Genome-wide association studies (GWAS) have identified the R47H variant of triggering receptor expressed on myeloid cell 2 (TREM2) as a risk factor for late-onset AD (LOAD) with an odds ratio of 4.5. TREM2 is an immunoreceptor primarily present on microglia in the CNS that binds to polyanionic molecules. The transmembrane domain of TREM2 signals through DAP12, an adaptor protein that contains an immunoreceptor tyrosine-based activation motif (ITAM), which mediates TREM2 signaling and promotes microglial activation and survival. In mouse models of AD, Trem2 haplodeficiency and deficiency lead to reduced microglial clustering around amyloid ß (Aß) plaques, suggesting TREM2 is required for plaque-associated microglial responses. Recently, TREM2 has been shown to enhance microglial metabolism through the mammalian target of rapamycin (mTOR) pathway. Although aberrant metabolism has long been associated with AD, not much was known regarding how metabolism in microglia might affect disease progression. In this review, we discuss the role of TREM2 and metabolism in AD pathology, highlighting how TREM2-mediated microglial metabolism modulates AD pathogenesis.
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Alzheimer's disease (AD) is a neurodegenerative disease that causes late-onset dementia. The R47H variant of the microglial receptor TREM2 triples AD risk in genome-wide association studies. In mouse AD models, TREM2-deficient microglia fail to proliferate and cluster around the amyloid-ß plaques characteristic of AD. In vitro, the common variant (CV) of TREM2 binds anionic lipids, whereas R47H mutation impairs binding. However, in vivo, the identity of TREM2 ligands and effect of the R47H variant remain unknown. We generated transgenic mice expressing human CV or R47H TREM2 and lacking endogenous TREM2 in the 5XFAD AD model. Only the CV transgene restored amyloid-ß-induced microgliosis and microglial activation, indicating that R47H impairs TREM2 function in vivo. Remarkably, soluble TREM2 was found on neurons and plaques in CV- but not R47H-expressing 5XFAD brains, although in vitro CV and R47H were shed similarly via Adam17 proteolytic activity. These results demonstrate that TREM2 interacts with neurons and plaques duing amyloid-ß accumulation and R47H impairs this interaction.