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1.
Geroscience ; 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38871964

RESUMO

Translational research is commonly performed in the C57B6/J mouse strain, chosen for its genetic homogeneity and phenotypic uniformity. Here, we evaluate the suitability of the white-footed deer mouse (Peromyscus leucopus) as a model organism for aging research, offering a comparative analysis against C57B6/J and diversity outbred (DO) Mus musculus strains. Our study includes comparisons of body composition, skeletal muscle function, and cardiovascular parameters, shedding light on potential applications and limitations of P. leucopus in aging studies. Notably, P. leucopus exhibits distinct body composition characteristics, emphasizing reduced muscle force exertion and a unique metabolism, particularly in fat mass. Cardiovascular assessments showed changes in arterial stiffness, challenging conventional assumptions and highlighting the need for a nuanced interpretation of aging-related phenotypes. Our study also highlights inherent challenges associated with maintaining and phenotyping P. leucopus cohorts. Behavioral considerations, including anxiety-induced responses during handling and phenotyping assessment, pose obstacles in acquiring meaningful data. Moreover, the unique anatomy of P. leucopus necessitates careful adaptation of protocols designed for Mus musculus. While showcasing potential benefits, further extensive analyses across broader age ranges and larger cohorts are necessary to establish the reliability of P. leucopus as a robust and translatable model for aging studies.

2.
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
3.
Nat Biotechnol ; 42(1): 109-118, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37106037

RESUMO

Molecular mechanisms of organismal and cell aging remain incompletely understood. We, therefore, generated a body-wide map of noncoding RNA (ncRNA) expression in aging (16 organs at ten timepoints from 1 to 27 months) and rejuvenated mice. We found molecular aging trajectories are largely tissue-specific except for eight broadly deregulated microRNAs (miRNAs). Their individual abundance mirrors their presence in circulating plasma and extracellular vesicles (EVs) whereas tissue-specific ncRNAs were less present. For miR-29c-3p, we observe the largest correlation with aging in solid organs, plasma and EVs. In mice rejuvenated by heterochronic parabiosis, miR-29c-3p was the most prominent miRNA restored to similar levels found in young liver. miR-29c-3p targets the extracellular matrix and secretion pathways, known to be implicated in aging. We provide a map of organism-wide expression of ncRNAs with aging and rejuvenation and identify a set of broadly deregulated miRNAs, which may function as systemic regulators of aging via plasma and EVs.


Assuntos
MicroRNAs , Camundongos , Animais , MicroRNAs/metabolismo , Envelhecimento/genética , Fígado/metabolismo , Parabiose
4.
bioRxiv ; 2023 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-37546938

RESUMO

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

5.
Nat Aging ; 3(1): 121-137, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-37118510

RESUMO

The diversity of cell types is a challenge for quantifying aging and its reversal. Here we develop 'aging clocks' based on single-cell transcriptomics to characterize cell-type-specific aging and rejuvenation. We generated single-cell transcriptomes from the subventricular zone neurogenic region of 28 mice, tiling ages from young to old. We trained single-cell-based regression models to predict chronological age and biological age (neural stem cell proliferation capacity). These aging clocks are generalizable to independent cohorts of mice, other regions of the brains, and other species. To determine if these aging clocks could quantify transcriptomic rejuvenation, we generated single-cell transcriptomic datasets of neurogenic regions for two interventions-heterochronic parabiosis and exercise. Aging clocks revealed that heterochronic parabiosis and exercise reverse transcriptomic aging in neurogenic regions, but in different ways. This study represents the first development of high-resolution aging clocks from single-cell transcriptomic data and demonstrates their application to quantify transcriptomic rejuvenation.


Assuntos
Envelhecimento , Rejuvenescimento , Camundongos , Animais , Envelhecimento/genética , Senescência Celular , Encéfalo , Neurogênese
6.
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
7.
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
8.
Nucleic Acids Res ; 50(D1): D211-D221, 2022 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-34570238

RESUMO

Small non-coding RNAs (sncRNAs) are pervasive regulators of physiological and pathological processes. We previously developed the human miRNA Tissue Atlas, detailing the expression of miRNAs across organs in the human body. Here, we present an updated resource containing sequencing data of 188 tissue samples comprising 21 organ types retrieved from six humans. Sampling the organs from the same bodies minimizes intra-individual variability and facilitates the making of a precise high-resolution body map of the non-coding transcriptome. The data allow shedding light on the organ- and organ system-specificity of piwi-interacting RNAs (piRNAs), transfer RNAs (tRNAs), microRNAs (miRNAs) and other non-coding RNAs. As use case of our resource, we describe the identification of highly specific ncRNAs in different organs. The update also contains 58 samples from six tissues of the Tabula Muris collection, allowing to check if the tissue specificity is evolutionary conserved between Homo sapiens and Mus musculus. The updated resource of 87 252 non-coding RNAs from nine non-coding RNA classes for all organs and organ systems is available online without any restrictions (https://www.ccb.uni-saarland.de/tissueatlas2).


Assuntos
MicroRNAs/genética , RNA Longo não Codificante/genética , RNA Interferente Pequeno/genética , RNA Nuclear Pequeno/genética , RNA Nucleolar Pequeno/genética , RNA de Transferência/genética , Software , Animais , Atlas como Assunto , Feminino , Humanos , Internet , Masculino , Camundongos , MicroRNAs/classificação , MicroRNAs/metabolismo , Especificidade de Órgãos , RNA Longo não Codificante/classificação , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/classificação , RNA Interferente Pequeno/metabolismo , RNA Nuclear Pequeno/classificação , RNA Nuclear Pequeno/metabolismo , RNA Nucleolar Pequeno/classificação , RNA Nucleolar Pequeno/metabolismo , RNA de Transferência/classificação , RNA de Transferência/metabolismo , Transcriptoma
10.
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
11.
Nat Commun ; 11(1): 5958, 2020 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-33235214

RESUMO

Aging is a key risk factor for chronic diseases of the elderly. MicroRNAs regulate post-transcriptional gene silencing through base-pair binding on their target mRNAs. We identified nonlinear changes in age-related microRNAs by analyzing whole blood from 1334 healthy individuals. We observed a larger influence of the age as compared to the sex and provide evidence for a shift to the 5' mature form of miRNAs in healthy aging. The addition of 3059 diseased patients uncovered pan-disease and disease-specific alterations in aging profiles. Disease biomarker sets for all diseases were different between young and old patients. Computational deconvolution of whole-blood miRNAs into blood cell types suggests that cell intrinsic gene expression changes may impart greater significance than cell abundance changes to the whole blood miRNA profile. Altogether, these data provide a foundation for understanding the relationship between healthy aging and disease, and for the development of age-specific disease biomarkers.


Assuntos
Envelhecimento/genética , Biomarcadores , MicroRNAs/sangue , Adulto , Idoso , Envelhecimento/metabolismo , Doença/genética , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Envelhecimento Saudável/genética , Humanos , Masculino , MicroRNAs/genética , RNA-Seq/métodos
12.
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
13.
Cell Rep ; 30(13): 4418-4432.e4, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32234477

RESUMO

Brain endothelial cells (BECs) are key constituents of the blood-brain barrier (BBB), protecting the brain from pathogens and restricting access of circulatory factors. Yet, because circulatory proteins have prominent age-related effects on adult neurogenesis, neuroinflammation, and cognitive function in mice, we wondered whether BECs receive and potentially relay signals between the blood and brain. Using single-cell RNA sequencing of hippocampal BECs, we discover that capillary BECs-compared with arterial and venous BECs-undergo the greatest transcriptional changes in normal aging, upregulating innate immunity and oxidative stress response pathways. Short-term infusions of aged plasma into young mice recapitulate key aspects of this aging transcriptome, and remarkably, infusions of young plasma into aged mice exert rejuvenation effects on the capillary transcriptome. Together, these findings suggest that the transcriptional age of BECs is exquisitely sensitive to age-related circulatory cues and pinpoint the BBB itself as a promising therapeutic target to treat brain disease.


Assuntos
Envelhecimento/fisiologia , Circulação Sanguínea/fisiologia , Encéfalo/citologia , Células Endoteliais/metabolismo , Envelhecimento/sangue , Envelhecimento/genética , Animais , Artérias/fisiologia , Capilares/fisiologia , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Transcrição Gênica/efeitos dos fármacos , Transcriptoma/genética , Veias/fisiologia
14.
Nat Med ; 25(12): 1843-1850, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31806903

RESUMO

Aging is a predominant risk factor for several chronic diseases that limit healthspan1. Mechanisms of aging are thus increasingly recognized as potential therapeutic targets. Blood from young mice reverses aspects of aging and disease across multiple tissues2-10, which supports a hypothesis that age-related molecular changes in blood could provide new insights into age-related disease biology. We measured 2,925 plasma proteins from 4,263 young adults to nonagenarians (18-95 years old) and developed a new bioinformatics approach that uncovered marked non-linear alterations in the human plasma proteome with age. Waves of changes in the proteome in the fourth, seventh and eighth decades of life reflected distinct biological pathways and revealed differential associations with the genome and proteome of age-related diseases and phenotypic traits. This new approach to the study of aging led to the identification of unexpected signatures and pathways that might offer potential targets for age-related diseases.


Assuntos
Envelhecimento/sangue , Proteínas Sanguíneas/genética , Longevidade/genética , Proteoma/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Animais , Doença Crônica , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
15.
Sci Rep ; 8(1): 2410, 2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29402901

RESUMO

Processes that have been linked to aging and cancer include an inflammatory milieu driven by senescent cells. Senescent cells lose the ability to divide, essentially irreversibly, and secrete numerous proteases, cytokines and growth factors, termed the senescence-associated secretory phenotype (SASP). Senescent cells that lack p53 tumor suppressor function show an exaggerated SASP, suggesting the SASP is negatively controlled by p53. Here, we show that increased p53 activity caused by small molecule inhibitors of MDM2, which promotes p53 degradation, reduces inflammatory cytokine production by senescent cells. Upon treatment with the MDM2 inhibitors nutlin-3a or MI-63, human cells acquired a senescence-like growth arrest, but the arrest was reversible. Importantly, the inhibitors reduced expression of the signature SASP factors IL-6 and IL-1α by cells made senescent by genotoxic stimuli, and suppressed the ability of senescent fibroblasts to stimulate breast cancer cell aggressiveness. Our findings suggest that MDM2 inhibitors could reduce cancer progression in part by reducing the pro-inflammatory environment created by senescent cells.


Assuntos
Senescência Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , Indóis/farmacologia , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/genética , Compostos de Espiro/farmacologia , Proteína Supressora de Tumor p53/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular , Senescência Celular/genética , Senescência Celular/efeitos da radiação , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/efeitos da radiação , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/efeitos da radiação , Prepúcio do Pênis/citologia , Raios gama , Humanos , Interleucina-1alfa/antagonistas & inibidores , Interleucina-1alfa/genética , Interleucina-1alfa/metabolismo , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Interleucina-6/metabolismo , Pulmão/citologia , Masculino , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/agonistas , Proteína Supressora de Tumor p53/metabolismo
16.
Arch Biochem Biophys ; 545: 44-52, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24418316

RESUMO

The amyloid ß-peptide (Aß) is a 40-42 residue peptide that is the principal toxic species in Alzheimer's disease (AD). The oxidation of methionine-35 (Met35) to the sulfoxide form (Met35(ox)) has been identified as potential modulator of Aß aggregation. The role Met35(ox) plays in Aß neurotoxicity differs among experimental studies, which may be due to inconsistent solution conditions (pH, buffer, temperature). We applied atomistic molecular dynamics (MD) simulations as a means to probe the dynamics of the monomeric 40-residue alloform of Aß (Aß40) containing Met35 or Met35(ox) in an effort to resolve the conflicting experimental results. We found that Met35 oxidation decreases the ß-strand content of the C-terminal hydrophobic region (residues 29-40), with a specific effect on the secondary structure of residues 33-35, thus potentially impeding aggregation. Further, there is an important interplay between oxidation state and solution conditions, with pH and salt concentration augmenting the effects of oxidation. The results presented here serve to rationalize the conflicting results seen in experimental studies and provide a fundamental biophysical characterization of monomeric Aß40 dynamics in both reduced and oxidized forms, providing insight into the biochemical mechanism of Aß40 and oxidative stress related to AD.


Assuntos
Peptídeos beta-Amiloides/química , Metionina/química , Fragmentos de Peptídeos/química , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Metionina/metabolismo , Simulação de Dinâmica Molecular , Oxirredução , Fragmentos de Peptídeos/metabolismo , Dobramento de Proteína , Estrutura Secundária de Proteína
17.
J Cell Biol ; 201(4): 613-29, 2013 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-23649808

RESUMO

Cellular senescence irreversibly arrests proliferation in response to potentially oncogenic stress. Senescent cells also secrete inflammatory cytokines such as IL-6, which promote age-associated inflammation and pathology. HMGB1 (high mobility group box 1) modulates gene expression in the nucleus, but certain immune cells secrete HMGB1 as an extracellular Alarmin to signal tissue damage. We show that nuclear HMGB1 relocalized to the extracellular milieu in senescent human and mouse cells in culture and in vivo. In contrast to cytokine secretion, HMGB1 redistribution required the p53 tumor suppressor, but not its activator ATM. Moreover, altered HMGB1 expression induced a p53-dependent senescent growth arrest. Senescent fibroblasts secreted oxidized HMGB1, which stimulated cytokine secretion through TLR-4 signaling. HMGB1 depletion, HMGB1 blocking antibody, or TLR-4 inhibition attenuated senescence-associated IL-6 secretion, and exogenous HMGB1 stimulated NF-κB activity and restored IL-6 secretion to HMGB1-depleted cells. Our findings identify senescence as a novel biological setting in which HMGB1 functions and link HMGB1 redistribution to p53 activity and senescence-associated inflammation.


Assuntos
Regulação da Expressão Gênica , Proteína HMGB1/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular/metabolismo , Núcleo Celular/metabolismo , Proliferação de Células , Senescência Celular , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Citocinas/metabolismo , Proteínas de Ligação a DNA/metabolismo , Fibroblastos/metabolismo , Humanos , Inflamação , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Proteínas Supressoras de Tumor/metabolismo
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