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1.
Cell ; 2024 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-39332414

RESUMO

In this high-throughput proteomic study of autosomal dominant Alzheimer's disease (ADAD), we sought to identify early biomarkers in cerebrospinal fluid (CSF) for disease monitoring and treatment strategies. We examined CSF proteins in 286 mutation carriers (MCs) and 177 non-carriers (NCs). The developed multi-layer regression model distinguished proteins with different pseudo-trajectories between these groups. We validated our findings with independent ADAD as well as sporadic AD datasets and employed machine learning to develop and validate predictive models. Our study identified 137 proteins with distinct trajectories between MCs and NCs, including eight that changed before traditional AD biomarkers. These proteins are grouped into three stages: early stage (stress response, glutamate metabolism, neuron mitochondrial damage), middle stage (neuronal death, apoptosis), and late presymptomatic stage (microglial changes, cell communication). The predictive model revealed a six-protein subset that more effectively differentiated MCs from NCs, compared with conventional biomarkers.

2.
Cell ; 186(19): 4117-4133.e22, 2023 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-37591239

RESUMO

Aging is the key risk factor for cognitive decline, yet the molecular changes underlying brain aging remain poorly understood. Here, we conducted spatiotemporal RNA sequencing of the mouse brain, profiling 1,076 samples from 15 regions across 7 ages and 2 rejuvenation interventions. Our analysis identified a brain-wide gene signature of aging in glial cells, which exhibited spatially defined changes in magnitude. By integrating spatial and single-nucleus transcriptomics, we found that glial aging was particularly accelerated in white matter compared with cortical regions, whereas specialized neuronal populations showed region-specific expression changes. Rejuvenation interventions, including young plasma injection and dietary restriction, exhibited distinct effects on gene expression in specific brain regions. Furthermore, we discovered differential gene expression patterns associated with three human neurodegenerative diseases, highlighting the importance of regional aging as a potential modulator of disease. Our findings identify molecular foci of brain aging, providing a foundation to target age-related cognitive decline.


Assuntos
Envelhecimento , Disfunção Cognitiva , Substância Branca , Animais , Humanos , Camundongos , Disfunção Cognitiva/genética , Perfilação da Expressão Gênica , Núcleo Solitário , Substância Branca/patologia , Análise da Expressão Gênica de Célula Única , Encéfalo/patologia
3.
Cell ; 185(26): 5028-5039.e13, 2022 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-36516855

RESUMO

Cerebrospinal fluid (CSF) contains a tightly regulated immune system. However, knowledge is lacking about how CSF immunity is altered with aging or neurodegenerative disease. Here, we performed single-cell RNA sequencing on CSF from 45 cognitively normal subjects ranging from 54 to 82 years old. We uncovered an upregulation of lipid transport genes in monocytes with age. We then compared this cohort with 14 cognitively impaired subjects. In cognitively impaired subjects, downregulation of lipid transport genes in monocytes occurred concomitantly with altered cytokine signaling to CD8 T cells. Clonal CD8 T effector memory cells upregulated C-X-C motif chemokine receptor 6 (CXCR6) in cognitively impaired subjects. The CXCR6 ligand, C-X-C motif chemokine ligand 16 (CXCL16), was elevated in the CSF of cognitively impaired subjects, suggesting CXCL16-CXCR6 signaling as a mechanism for antigen-specific T cell entry into the brain. Cumulatively, these results reveal cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doenças Neurodegenerativas , Humanos , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Ligantes , Encéfalo , Envelhecimento , Lipídeos , Biomarcadores
4.
Immunity ; 56(9): 2121-2136.e6, 2023 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-37659412

RESUMO

Genetic association studies have demonstrated the critical involvement of the microglial immune response in Alzheimer's disease (AD) pathogenesis. Phospholipase C-gamma-2 (PLCG2) is selectively expressed by microglia and functions in many immune receptor signaling pathways. In AD, PLCG2 is induced uniquely in plaque-associated microglia. A genetic variant of PLCG2, PLCG2P522R, is a mild hypermorph that attenuates AD risk. Here, we identified a loss-of-function PLCG2 variant, PLCG2M28L, that confers an increased AD risk. PLCG2P522R attenuated disease in an amyloidogenic murine AD model, whereas PLCG2M28L exacerbated the plaque burden associated with altered phagocytosis and Aß clearance. The variants bidirectionally modulated disease pathology by inducing distinct transcriptional programs that identified microglial subpopulations associated with protective or detrimental phenotypes. These findings identify PLCG2M28L as a potential AD risk variant and demonstrate that PLCG2 variants can differentially orchestrate microglial responses in AD pathogenesis that can be therapeutically targeted.


Assuntos
Doença de Alzheimer , Animais , Camundongos , Doença de Alzheimer/genética , Estudos de Associação Genética , Microglia , Fagocitose/genética , Fenótipo , Placa Amiloide , Fosfolipase C gama/metabolismo
5.
Nature ; 628(8006): 154-161, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38480892

RESUMO

Several genetic risk factors for Alzheimer's disease implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells1. However, the relationship between lipid metabolism in glia and Alzheimer's disease pathology remains poorly understood. Through single-nucleus RNA sequencing of brain tissue in Alzheimer's disease, we have identified a microglial state defined by the expression of the lipid droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant in patients with Alzheimer's disease having the APOE4/4 genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aß induces ACSL1 expression, triglyceride synthesis and lipid droplet accumulation in an APOE-dependent manner. Additionally, conditioned media from lipid droplet-containing microglia lead to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for Alzheimer's disease with microglial lipid droplet accumulation and neurotoxic microglia-derived factors, potentially providing therapeutic strategies for Alzheimer's disease.


Assuntos
Doença de Alzheimer , Apolipoproteína E4 , Gotículas Lipídicas , Microglia , Animais , Feminino , Humanos , Masculino , Camundongos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Gotículas Lipídicas/metabolismo , Gotículas Lipídicas/patologia , Microglia/citologia , Microglia/metabolismo , Microglia/patologia , Triglicerídeos , Proteínas tau , Meios de Cultivo Condicionados , Fosforilação , Predisposição Genética para Doença
6.
Cell ; 159(4): 709-13, 2014 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-25417146

RESUMO

Mammalian aging can be delayed with genetic, dietary, and pharmacologic approaches. Given that the elderly population is dramatically increasing and that aging is the greatest risk factor for a majority of chronic diseases driving both morbidity and mortality, it is critical to expand geroscience research directed at extending human healthspan.


Assuntos
Envelhecimento/fisiologia , Doença Crônica , Envelhecimento/patologia , Animais , Pesquisa Biomédica , Epigênese Genética , Interação Gene-Ambiente , Humanos
7.
Nature ; 624(7990): 164-172, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38057571

RESUMO

Animal studies show aging varies between individuals as well as between organs within an individual1-4, but whether this is true in humans and its effect on age-related diseases is unknown. We utilized levels of human blood plasma proteins originating from specific organs to measure organ-specific aging differences in living individuals. Using machine learning models, we analysed aging in 11 major organs and estimated organ age reproducibly in five independent cohorts encompassing 5,676 adults across the human lifespan. We discovered nearly 20% of the population show strongly accelerated age in one organ and 1.7% are multi-organ agers. Accelerated organ aging confers 20-50% higher mortality risk, and organ-specific diseases relate to faster aging of those organs. We find individuals with accelerated heart aging have a 250% increased heart failure risk and accelerated brain and vascular aging predict Alzheimer's disease (AD) progression independently from and as strongly as plasma pTau-181 (ref. 5), the current best blood-based biomarker for AD. Our models link vascular calcification, extracellular matrix alterations and synaptic protein shedding to early cognitive decline. We introduce a simple and interpretable method to study organ aging using plasma proteomics data, predicting diseases and aging effects.


Assuntos
Envelhecimento , Biomarcadores , Doença , Saúde , Especificidade de Órgãos , Proteoma , Proteômica , Adulto , Humanos , Envelhecimento/sangue , Doença de Alzheimer/sangue , Biomarcadores/sangue , Encéfalo/metabolismo , Disfunção Cognitiva/sangue , Proteoma/análise , Aprendizado de Máquina , Estudos de Coortes , Progressão da Doença , Insuficiência Cardíaca/sangue , Matriz Extracelular/metabolismo , Sinapses/metabolismo , Calcificação Vascular/sangue , Coração
8.
Immunity ; 50(6): 1349-1351, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31216459

RESUMO

To gain unfettered insight into one of the scourges of our aging societies, Mathys and colleagues in Nature (Mathys et al., 2019) illuminate the brain transcriptome of Alzheimer's disease at single-cell resolution. Their findings implicate oligodendrocytes, a cell type largely neglected in Alzheimer's disease research, and sex in the disease in intriguing ways.


Assuntos
Doença de Alzheimer , Encéfalo , Humanos , Transcriptoma
9.
Nat Rev Genet ; 23(12): 715-727, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35715611

RESUMO

Age is the key risk factor for diseases and disabilities of the elderly. Efforts to tackle age-related diseases and increase healthspan have suggested targeting the ageing process itself to 'rejuvenate' physiological functioning. However, achieving this aim requires measures of biological age and rates of ageing at the molecular level. Spurred by recent advances in high-throughput omics technologies, a new generation of tools to measure biological ageing now enables the quantitative characterization of ageing at molecular resolution. Epigenomic, transcriptomic, proteomic and metabolomic data can be harnessed with machine learning to build 'ageing clocks' with demonstrated capacity to identify new biomarkers of biological ageing.


Assuntos
Envelhecimento , Proteômica , Humanos , Idoso , Envelhecimento/genética , Biomarcadores , Epigenômica , Metabolômica
10.
Nature ; 603(7900): 309-314, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35236985

RESUMO

The ability to slow or reverse biological ageing would have major implications for mitigating disease risk and maintaining vitality1. Although an increasing number of interventions show promise for rejuvenation2, their effectiveness on disparate cell types across the body and the molecular pathways susceptible to rejuvenation remain largely unexplored. Here we performed single-cell RNA sequencing on 20 organs to reveal cell-type-specific responses to young and aged blood in heterochronic parabiosis. Adipose mesenchymal stromal cells, haematopoietic stem cells and hepatocytes are among those cell types that are especially responsive. On the pathway level, young blood invokes new gene sets in addition to reversing established ageing patterns, with the global rescue of genes encoding electron transport chain subunits pinpointing a prominent role of mitochondrial function in parabiosis-mediated rejuvenation. We observed an almost universal loss of gene expression with age that is largely mimicked by parabiosis: aged blood reduces global gene expression, and young blood restores it in select cell types. Together, these data lay the groundwork for a systemic understanding of the interplay between blood-borne factors and cellular integrity.


Assuntos
Parabiose , Análise de Célula Única , Adipócitos , Envelhecimento/genética , Transporte de Elétrons/genética , Células-Tronco Hematopoéticas , Hepatócitos , Células-Tronco Mesenquimais , Mitocôndrias , Especificidade de Órgãos/genética , RNA-Seq , Rejuvenescimento
11.
Nature ; 603(7903): 885-892, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35165441

RESUMO

The human brain vasculature is of great medical importance: its dysfunction causes disability and death1, and the specialized structure it forms-the blood-brain barrier-impedes the treatment of nearly all brain disorders2,3. Yet so far, we have no molecular map of the human brain vasculature. Here we develop vessel isolation and nuclei extraction for sequencing (VINE-seq) to profile the major vascular and perivascular cell types of the human brain through 143,793 single-nucleus transcriptomes from 25 hippocampus and cortex samples of 9 individuals with Alzheimer's disease and 8 individuals with no cognitive impairment. We identify brain-region- and species-enriched genes and pathways. We reveal molecular principles of human arteriovenous organization, recapitulating a gradual endothelial and punctuated mural cell continuum. We discover two subtypes of human pericytes, marked by solute transport and extracellular matrix (ECM) organization; and define perivascular versus meningeal fibroblast specialization. In Alzheimer's disease, we observe selective vulnerability of ECM-maintaining pericytes and gene expression patterns that implicate dysregulated blood flow. With an expanded survey of brain cell types, we find that 30 of the top 45 genes that have been linked to Alzheimer's disease risk by genome-wide association studies (GWASs) are expressed in the human brain vasculature, and we confirm this by immunostaining. Vascular GWAS genes map to endothelial protein transport, adaptive immune and ECM pathways. Many are microglia-specific in mice, suggesting a partial evolutionary transfer of Alzheimer's disease risk. Our work uncovers the molecular basis of the human brain vasculature, which will inform our understanding of overall brain health, disease and therapy.


Assuntos
Doença de Alzheimer , Encéfalo , Suscetibilidade a Doenças , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Animais , Encéfalo/irrigação sanguínea , Encéfalo/citologia , Encéfalo/metabolismo , Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Estudo de Associação Genômica Ampla , Hipocampo/irrigação sanguínea , Hipocampo/citologia , Hipocampo/metabolismo , Humanos , Camundongos , Microglia/metabolismo , Pericitos/metabolismo , Transcriptoma
12.
Nature ; 605(7910): 509-515, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35545674

RESUMO

Recent understanding of how the systemic environment shapes the brain throughout life has led to numerous intervention strategies to slow brain ageing1-3. Cerebrospinal fluid (CSF) makes up the immediate environment of brain cells, providing them with nourishing compounds4,5. We discovered that infusing young CSF directly into aged brains improves memory function. Unbiased transcriptome analysis of the hippocampus identified oligodendrocytes to be most responsive to this rejuvenated CSF environment. We further showed that young CSF boosts oligodendrocyte progenitor cell (OPC) proliferation and differentiation in the aged hippocampus and in primary OPC cultures. Using SLAMseq to metabolically label nascent mRNA, we identified serum response factor (SRF), a transcription factor that drives actin cytoskeleton rearrangement, as a mediator of OPC proliferation following exposure to young CSF. With age, SRF expression decreases in hippocampal OPCs, and the pathway is induced by acute injection with young CSF. We screened for potential SRF activators in CSF and found that fibroblast growth factor 17 (Fgf17) infusion is sufficient to induce OPC proliferation and long-term memory consolidation in aged mice while Fgf17 blockade impairs cognition in young mice. These findings demonstrate the rejuvenating power of young CSF and identify Fgf17 as a key target to restore oligodendrocyte function in the ageing brain.


Assuntos
Envelhecimento , Encéfalo , Líquido Cefalorraquidiano , Células Precursoras de Oligodendrócitos , Oligodendroglia , Animais , Diferenciação Celular/genética , Líquido Cefalorraquidiano/fisiologia , Fatores de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica , Camundongos , Células Precursoras de Oligodendrócitos/metabolismo , Oligodendroglia/metabolismo
13.
Nature ; 595(7868): 565-571, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34153974

RESUMO

Although SARS-CoV-2 primarily targets the respiratory system, patients with and survivors of COVID-19 can suffer neurological symptoms1-3. However, an unbiased understanding of the cellular and molecular processes that are affected in the brains of patients with COVID-19 is missing. Here we profile 65,309 single-nucleus transcriptomes from 30 frontal cortex and choroid plexus samples across 14 control individuals (including 1 patient with terminal influenza) and 8 patients with COVID-19. Although our systematic analysis yields no molecular traces of SARS-CoV-2 in the brain, we observe broad cellular perturbations indicating that barrier cells of the choroid plexus sense and relay peripheral inflammation into the brain and show that peripheral T cells infiltrate the parenchyma. We discover microglia and astrocyte subpopulations associated with COVID-19 that share features with pathological cell states that have previously been reported in human neurodegenerative disease4-6. Synaptic signalling of upper-layer excitatory neurons-which are evolutionarily expanded in humans7 and linked to cognitive function8-is preferentially affected in COVID-19. Across cell types, perturbations associated with COVID-19 overlap with those found in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia and depression. Our findings and public dataset provide a molecular framework to understand current observations of COVID-19-related neurological disease, and any such disease that may emerge at a later date.


Assuntos
Astrócitos/patologia , Encéfalo/patologia , COVID-19/diagnóstico , COVID-19/patologia , Plexo Corióideo/patologia , Microglia/patologia , Neurônios/patologia , Idoso , Idoso de 80 Anos ou mais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Encéfalo/virologia , COVID-19/genética , COVID-19/fisiopatologia , Núcleo Celular/genética , Plexo Corióideo/metabolismo , Plexo Corióideo/fisiopatologia , Plexo Corióideo/virologia , Feminino , Humanos , Inflamação/virologia , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/crescimento & desenvolvimento , SARS-CoV-2/patogenicidade , Análise de Célula Única , Transcriptoma , Replicação Viral
14.
Nature ; 600(7889): 494-499, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34880498

RESUMO

Physical exercise is generally beneficial to all aspects of human and animal health, slowing cognitive ageing and neurodegeneration1. The cognitive benefits of physical exercise are tied to an increased plasticity and reduced inflammation within the hippocampus2-4, yet little is known about the factors and mechanisms that mediate these effects. Here we show that 'runner plasma', collected from voluntarily running mice and infused into sedentary mice, reduces baseline neuroinflammatory gene expression and experimentally induced brain inflammation. Plasma proteomic analysis revealed a concerted increase in complement cascade inhibitors including clusterin (CLU). Intravenously injected CLU binds to brain endothelial cells and reduces neuroinflammatory gene expression in a mouse model of acute brain inflammation and a mouse model of Alzheimer's disease. Patients with cognitive impairment who participated in structured exercise for 6 months had higher plasma levels of CLU. These findings demonstrate the existence of anti-inflammatory exercise factors that are transferrable, target the cerebrovasculature and benefit the brain, and are present in humans who engage in exercise.


Assuntos
Doença de Alzheimer , Encefalite , Doença de Alzheimer/metabolismo , Animais , Clusterina/genética , Clusterina/metabolismo , Células Endoteliais/metabolismo , Humanos , Camundongos , Proteômica
15.
Proc Natl Acad Sci U S A ; 121(12): e2307250121, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38483990

RESUMO

Myelination of neuronal axons is essential for nervous system development. Myelination requires dramatic cytoskeletal dynamics in oligodendrocytes, but how actin is regulated during myelination is poorly understood. We recently identified serum response factor (SRF)-a transcription factor known to regulate expression of actin and actin regulators in other cell types-as a critical driver of myelination in the aged brain. Yet, a major gap remains in understanding the mechanistic role of SRF in oligodendrocyte lineage cells. Here, we show that SRF is required cell autonomously in oligodendrocytes for myelination during development. Combining ChIP-seq with RNA-seq identifies SRF-target genes in oligodendrocyte precursor cells and oligodendrocytes that include actin and other key cytoskeletal genes. Accordingly, SRF knockout oligodendrocytes exhibit dramatically reduced actin filament levels early in differentiation, consistent with its role in actin-dependent myelin sheath initiation. Surprisingly, oligodendrocyte-restricted loss of SRF results in upregulation of gene signatures associated with aging and neurodegenerative diseases. Together, our findings identify SRF as a transcriptional regulator that controls the expression of cytoskeletal genes required in oligodendrocytes for myelination. This study identifies an essential pathway regulating oligodendrocyte biology with high relevance to brain development, aging, and disease.


Assuntos
Actinas , Fator de Resposta Sérica , Actinas/genética , Actinas/metabolismo , Fator de Resposta Sérica/genética , Fator de Resposta Sérica/metabolismo , Oligodendroglia/metabolismo , Bainha de Mielina/genética , Bainha de Mielina/metabolismo , Citoesqueleto/genética , Diferenciação Celular/genética
16.
Nature ; 577(7790): 399-404, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31915375

RESUMO

Alzheimer's disease is an incurable neurodegenerative disorder in which neuroinflammation has a critical function1. However, little is known about the contribution of the adaptive immune response in Alzheimer's disease2. Here, using integrated analyses of multiple cohorts, we identify peripheral and central adaptive immune changes in Alzheimer's disease. First, we performed mass cytometry of peripheral blood mononuclear cells and discovered an immune signature of Alzheimer's disease that consists of increased numbers of CD8+ T effector memory CD45RA+ (TEMRA) cells. In a second cohort, we found that CD8+ TEMRA cells were negatively associated with cognition. Furthermore, single-cell RNA sequencing revealed that T cell receptor (TCR) signalling was enhanced in these cells. Notably, by using several strategies of single-cell TCR sequencing in a third cohort, we discovered clonally expanded CD8+ TEMRA cells in the cerebrospinal fluid of patients with Alzheimer's disease. Finally, we used machine learning, cloning and peptide screens to demonstrate the specificity of clonally expanded TCRs in the cerebrospinal fluid of patients with Alzheimer's disease to two separate Epstein-Barr virus antigens. These results reveal an adaptive immune response in the blood and cerebrospinal fluid in Alzheimer's disease and provide evidence of clonal, antigen-experienced T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration.


Assuntos
Doença de Alzheimer/imunologia , Linfócitos T CD8-Positivos/imunologia , Líquido Cefalorraquidiano/imunologia , Idoso , Sequência de Aminoácidos , Estudos de Coortes , Humanos , Memória Imunológica , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/imunologia , Análise de Sequência de Proteína
17.
Nature ; 583(7816): 425-430, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32612231

RESUMO

The vascular interface of the brain, known as the blood-brain barrier (BBB), is understood to maintain brain function in part via its low transcellular permeability1-3. Yet, recent studies have demonstrated that brain ageing is sensitive to circulatory proteins4,5. Thus, it is unclear whether permeability to individually injected exogenous tracers-as is standard in BBB studies-fully represents blood-to-brain transport. Here we label hundreds of proteins constituting the mouse blood plasma proteome, and upon their systemic administration, study the BBB with its physiological ligand. We find that plasma proteins readily permeate the healthy brain parenchyma, with transport maintained by BBB-specific transcriptional programmes. Unlike IgG antibody, plasma protein uptake diminishes in the aged brain, driven by an age-related shift in transport from ligand-specific receptor-mediated to non-specific caveolar transcytosis. This age-related shift occurs alongside a specific loss of pericyte coverage. Pharmacological inhibition of the age-upregulated phosphatase ALPL, a predicted negative regulator of transport, enhances brain uptake of therapeutically relevant transferrin, transferrin receptor antibody and plasma. These findings reveal the extent of physiological protein transcytosis to the healthy brain, a mechanism of widespread BBB dysfunction with age and a strategy for enhanced drug delivery.


Assuntos
Envelhecimento/metabolismo , Envelhecimento/patologia , Barreira Hematoencefálica/metabolismo , Transcitose , Fosfatase Alcalina/metabolismo , Animais , Anticorpos/metabolismo , Transporte Biológico , Proteínas Sanguíneas/administração & dosagem , Proteínas Sanguíneas/metabolismo , Proteínas Sanguíneas/farmacocinética , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Sistemas de Liberação de Medicamentos , Saúde , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasma/metabolismo , Proteoma/administração & dosagem , Proteoma/metabolismo , Proteoma/farmacocinética , Receptores da Transferrina/imunologia , Transcrição Gênica , Transferrina/metabolismo
18.
Nature ; 583(7817): 596-602, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32669715

RESUMO

Ageing is the single greatest cause of disease and death worldwide, and understanding the associated processes could vastly improve quality of life. Although major categories of ageing damage have been identified-such as altered intercellular communication, loss of proteostasis and eroded mitochondrial function1-these deleterious processes interact with extraordinary complexity within and between organs, and a comprehensive, whole-organism analysis of ageing dynamics has been lacking. Here we performed bulk RNA sequencing of 17 organs and plasma proteomics at 10 ages across the lifespan of Mus musculus, and integrated these findings with data from the accompanying Tabula Muris Senis2-or 'Mouse Ageing Cell Atlas'-which follows on from the original Tabula Muris3. We reveal linear and nonlinear shifts in gene expression during ageing, with the associated genes clustered in consistent trajectory groups with coherent biological functions-including extracellular matrix regulation, unfolded protein binding, mitochondrial function, and inflammatory and immune response. Notably, these gene sets show similar expression across tissues, differing only in the amplitude and the age of onset of expression. Widespread activation of immune cells is especially pronounced, and is first detectable in white adipose depots during middle age. Single-cell RNA sequencing confirms the accumulation of T cells and B cells in adipose tissue-including plasma cells that express immunoglobulin J-which also accrue concurrently across diverse organs. Finally, we show how gene expression shifts in distinct tissues are highly correlated with corresponding protein levels in plasma, thus potentially contributing to the ageing of the systemic circulation. Together, these data demonstrate a similar yet asynchronous inter- and intra-organ progression of ageing, providing a foundation from which to track systemic sources of declining health at old age.


Assuntos
Envelhecimento/genética , Envelhecimento/fisiologia , Regulação da Expressão Gênica , Especificidade de Órgãos/genética , Animais , Proteínas Sanguíneas/análise , Proteínas Sanguíneas/genética , Feminino , Cadeias J de Imunoglobulina/genética , Cadeias J de Imunoglobulina/metabolismo , Masculino , Camundongos , Plasmócitos/citologia , Plasmócitos/metabolismo , RNA Mensageiro/análise , RNA Mensageiro/genética , RNA-Seq , Análise de Célula Única , Linfócitos T/citologia , Linfócitos T/metabolismo , Fatores de Tempo , Transcriptoma
19.
Nucleic Acids Res ; 52(D1): D1089-D1096, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-37941147

RESUMO

The molecular causes and mechanisms of neurodegenerative diseases remain poorly understood. A growing number of single-cell studies have implicated various neural, glial, and immune cell subtypes to affect the mammalian central nervous system in many age-related disorders. Integrating this body of transcriptomic evidence into a comprehensive and reproducible framework poses several computational challenges. Here, we introduce ZEBRA, a large single-cell and single-nucleus RNA-seq database. ZEBRA integrates and normalizes gene expression and metadata from 33 studies, encompassing 4.2 million human and mouse brain cells sampled from 39 brain regions. It incorporates samples from patients with neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, and Multiple sclerosis, as well as samples from relevant mouse models. We employed scVI, a deep probabilistic auto-encoder model, to integrate the samples and curated both cell and sample metadata for downstream analysis. ZEBRA allows for cell-type and disease-specific markers to be explored and compared between sample conditions and brain regions, a cell composition analysis, and gene-wise feature mappings. Our comprehensive molecular database facilitates the generation of data-driven hypotheses, enhancing our understanding of mammalian brain function during aging and disease. The data sets, along with an interactive database are freely available at https://www.ccb.uni-saarland.de/zebra.


Assuntos
Doenças Neurodegenerativas , Análise de Célula Única , Animais , Humanos , Camundongos , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Doenças Neurodegenerativas/genética , Doença de Parkinson/metabolismo , Transcriptoma , Expressão Gênica
20.
Nat Rev Neurosci ; 21(5): 298, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32203300

RESUMO

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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