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1.
Nat Commun ; 14(1): 7086, 2023 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-37925537

RESUMO

Alternative lengthening of telomeres (ALT) is a telomere maintenance mechanism activated in ~10-15% of cancers, characterized by telomeric damage. Telomeric damage-induced long non-coding RNAs (dilncRNAs) are transcribed at dysfunctional telomeres and contribute to telomeric DNA damage response (DDR) activation and repair. Here we observed that telomeric dilncRNAs are preferentially elevated in ALT cells. Inhibition of C-rich (teloC) dilncRNAs with antisense oligonucleotides leads to DNA replication stress responses, increased genomic instability, and apoptosis induction selectively in ALT cells. Cell death is dependent on DNA replication and is increased by DNA replication stress. Mechanistically, teloC dilncRNA inhibition reduces RAD51 and 53BP1 recruitment to telomeres, boosts the engagement of BIR machinery, and increases C-circles and telomeric sister chromatid exchanges, without increasing telomeric non-S phase synthesis. These results indicate that teloC dilncRNA is necessary for a coordinated recruitment of DDR factors to ALT telomeres and it is essential for ALT cancer cells survival.


Assuntos
Telomerase , Homeostase do Telômero , Homeostase do Telômero/genética , Replicação do DNA , RNA , Sobrevivência Celular/genética , Telômero/genética , Telômero/metabolismo , Telomerase/genética , Telomerase/metabolismo
2.
Mol Cancer Ther ; 22(6): 737-750, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-37070671

RESUMO

A select group of patients with hepatocellular carcinomas (HCC) benefit from surgical, radiologic, and systemic therapies that include a combination of anti-angiogenic and immune-checkpoint inhibitors. However, because HCC is generally asymptomatic in its early stages, this not only leads to late diagnosis, but also to therapy resistance. The nucleoside analogue 6-thio-dG (THIO) is a first-in-class telomerase-mediated telomere-targeting anticancer agent. In telomerase expressing cancer cells, THIO is converted into the corresponding 5'-triphosphate, which is efficiently incorporated into telomeres by telomerase, activating telomere damage responses and apoptotic pathways. Here, we show how THIO is effective in controlling tumor growth and, when combined with immune checkpoint inhibitors, is even more effective in a T-cell-dependent manner. We also show telomere stress induced by THIO increases both innate sensing and adaptive antitumor immunity in HCC. Importantly, the extracellular high-mobility group box 1 protein acts as a prototypical endogenous DAMP (Damage Associated Molecular Pattern) in eliciting adaptive immunity by THIO. These results provide a strong rationale for combining telomere-targeted therapy with immunotherapy.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Telomerase , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Telomerase/genética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Telômero/genética , Imunidade Adaptativa
3.
J Cell Biol ; 220(6)2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-33851958

RESUMO

It is well established that short telomeres activate an ATM-driven DNA damage response that leads to senescence in terminally differentiated cells. However, technical limitations have hampered our understanding of how telomere shortening is signaled in human stem cells. Here, we show that telomere attrition induces ssDNA accumulation (G-strand) at telomeres in human pluripotent stem cells (hPSCs), but not in their differentiated progeny. This led to a unique role for ATR in the response of hPSCs to telomere shortening that culminated in an extended S/G2 cell cycle phase and a longer period of mitosis, which was associated with aneuploidy and mitotic catastrophe. Loss of p53 increased resistance to death, at the expense of increased mitotic abnormalities in hPSCs. Taken together, our data reveal an unexpected dominant role of ATR in hPSCs, combined with unique cell cycle abnormalities and, ultimately, consequences distinct from those observed in their isogenic differentiated counterparts.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteínas de Ciclo Celular/metabolismo , Ciclo Celular , Mitose , Células-Tronco Pluripotentes/patologia , Telômero/fisiologia , Proteína Supressora de Tumor p53/metabolismo , Aneuploidia , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas de Ciclo Celular/genética , Dano ao DNA , Humanos , Células-Tronco Pluripotentes/metabolismo , Proteína Supressora de Tumor p53/genética
5.
FASEB J ; 34(1): 386-398, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914653

RESUMO

To date, there is no direct evidence of telomerase activity in adult lung epithelial cells, but typical culture conditions only support cell proliferation for 30-40 population doublings (PD), a point at which telomeres remain relatively long. Here we report that in in vitro low stress culture conditions consisting of a fibroblast feeder layer, rho-associated coiled coil protein kinase inhibitor (ROCKi), and low oxygen (2%), normal human bronchial epithelial basal progenitor cells (HBECs) divide for over 200 PD without engaging a telomere maintenance mechanism (almost four times the "Hayflick limit"). HBECs exhibit critically short telomeres at 200 PD and the population of cells start to undergo replicative senescence. Subcloning these late passage cells to clonal density, to mimic lung injury in vivo, selects for rare subsets of HBECs that activate low levels of telomerase activity to maintain short telomeres. CRISPR/Cas9 knockout of human telomerase reverse transcriptase or treatment with the telomerase-mediated telomere targeting agent 6-thio-2'deoxyguanosine abrogates colony growth in these late passage cultures (>200 PD) but not in early passage cultures (<200 PD). To our knowledge, this is the first study to report such long-term growth of HBECs without a telomere maintenance mechanism. This report also provides direct evidence of telomerase activation in HBECs near senescence when telomeres are critically short. This novel cell culture system provides an experimental model to understand how telomerase is regulated in normal adult tissues.


Assuntos
Brônquios/citologia , Técnicas de Cultura de Células/métodos , Proliferação de Células , Senescência Celular , Células Epiteliais/citologia , Fibroblastos/citologia , Telômero/fisiologia , Adulto , Brônquios/fisiologia , Divisão Celular , Células Cultivadas , Células Epiteliais/fisiologia , Fibroblastos/fisiologia , Humanos , Telomerase/metabolismo , Encurtamento do Telômero
6.
Genome Res ; 29(11): 1878-1888, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31548359

RESUMO

Mitochondria are involved in a number of diverse cellular functions, including energy production, metabolic regulation, apoptosis, calcium homeostasis, cell proliferation, and motility, as well as free radical generation. Mitochondrial DNA (mtDNA) is present at hundreds to thousands of copies per cell in a tissue-specific manner. mtDNA copy number also varies during aging and disease progression and therefore might be considered as a biomarker that mirrors alterations within the human body. Here, we present a new quantitative, highly sensitive droplet digital PCR (ddPCR) method, droplet digital mitochondrial DNA measurement (ddMDM), to measure mtDNA copy number not only from cell populations but also from single cells. Our developed assay can generate data in as little as 3 h, is optimized for 96-well plates, and also allows the direct use of cell lysates without the need for DNA purification or nuclear reference genes. We show that ddMDM is able to detect differences between samples whose mtDNA copy number was close enough as to be indistinguishable by other commonly used mtDNA quantitation methods. By utilizing ddMDM, we show quantitative changes in mtDNA content per cell across a wide variety of physiological contexts including cancer progression, cell cycle progression, human T cell activation, and human aging.


Assuntos
Variações do Número de Cópias de DNA , DNA Mitocondrial/genética , Reação em Cadeia da Polimerase/métodos , Análise de Célula Única/métodos , Adulto , Idoso , Humanos , Limite de Detecção , Ativação Linfocitária , Linfócitos T/imunologia
7.
Aging Cell ; 18(4): e12979, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31152494

RESUMO

Hutchinson-Gilford progeria syndrome (HGPS) is characterized by accelerated senescence due to a de novo mutation in the LMNA gene. The mutation produces an abnormal lamin A protein called progerin that lacks the splice site necessary to remove a farnesylated domain. Subsequently, progerin accumulates in the nuclear envelope, disrupting nuclear architecture, chromatin organization, and gene expression. These alterations are often associated with rapid telomere erosion and cellular aging. Here, we further characterize the cellular and molecular abnormalities in HGPS cells and report a significant reversal of some of these abnormalities by introduction of in vitro transcribed and purified human telomerase (hTERT) mRNA. There is intra-individual heterogeneity of expression of telomere-associated proteins DNA PKcs/Ku70/Ku80, with low-expressing cells having shorter telomeres. In addition, the loss of the heterochromatin marker H3K9me3 in progeria is associated with accelerated telomere erosion. In HGPS cell lines characterized by short telomeres, transient transfections with hTERT mRNA increase telomere length, increase expression of telomere-associated proteins, increase proliferative capacity and cellular lifespan, and reverse manifestations of cellular senescence as assessed by ß-galactosidase expression and secretion of inflammatory cytokines. Unexpectedly, mRNA hTERT also improves nuclear morphology. In combination with the farnesyltransferase inhibitor (FTI) lonafarnib, hTERT mRNA promotes HGPS cell proliferation. Our findings demonstrate transient expression of human telomerase in combination with FTIs could represent an improved therapeutic approach for HGPS.


Assuntos
Fibroblastos/metabolismo , Progéria/metabolismo , RNA Mensageiro/metabolismo , Telomerase/metabolismo , Adolescente , Adulto , Idoso , Linhagem Celular , Senescência Celular/genética , Criança , Pré-Escolar , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Farnesiltranstransferase/antagonistas & inibidores , Feminino , Fibroblastos/efeitos dos fármacos , Humanos , Lactente , Recém-Nascido , Lamina Tipo A/metabolismo , Masculino , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Progéria/tratamento farmacológico , Progéria/patologia , Piridinas/farmacologia , Piridinas/uso terapêutico , RNA Mensageiro/genética , Telomerase/genética , Telômero/metabolismo , Homeostase do Telômero/efeitos dos fármacos , Homeostase do Telômero/genética , Transfecção
8.
Aging Cell ; 18(1): e12859, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30488553

RESUMO

It is generally recognized that the function of the immune system declines with increased age and one of the major immune changes is impaired T-cell responses upon antigen presentation/stimulation. Some "high-performing" centenarians (100+ years old) are remarkably successful in escaping, or largely postponing, major age-related diseases. However, the majority of centenarians ("low-performing") have experienced these pathologies and are forced to reside in long-term nursing facilities. Previous studies have pooled all centenarians examining heterogeneous populations of resting/unstimulated peripheral blood mononuclear cells (PBMCs). T cells represent around 60% of PBMC and are in a quiescence state when unstimulated. However, upon stimulation, T cells rapidly divide and exhibit dramatic changes in gene expression. We have compared stimulated T-cell responses and identified a set of transcripts expressed in vitro that are dramatically different in high- vs. low-performing centenarians. We have also identified several other measurements that are different between high- and low-performing centenarians: (a) The amount of proliferation following in vitro stimulation is dramatically greater in high-performing centenarians compared to 67- to 83-year-old controls and low-performing centenarians; (b) telomere length is greater in the high-performing centenarians; and (c) telomerase activity following stimulation is greater in the high-performing centenarians. In addition, we have validated a number of genes whose expression is directly related to telomere length and these are potential fundamental biomarkers of aging that may influence the risk and progression of multiple aging conditions.


Assuntos
Linfócitos T/metabolismo , Telomerase/metabolismo , Homeostase do Telômero , Telômero/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Biomarcadores/metabolismo , Proliferação de Células , Replicação do DNA , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Genoma Humano , Humanos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
Oncogene ; 38(16): 2937-2952, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30568224

RESUMO

Alternative splicing is dysregulated in cancer cells, driving the production of isoforms that allow tumor cells to survive and continuously proliferate. Part of the reactivation of telomerase involves the splicing of hTERT transcripts to produce full-length (FL) TERT. Very few splicing factors to date have been described to interact with hTERT and promote the production of FL TERT. We recently described one such splicing factor, NOVA1, that acts as an enhancer of FL hTERT splicing, increases telomerase activity, and promotes telomere maintenance in cancer cells. NOVA1 is expressed primarily in neurons and is involved in neurogenesis. In the present studies, we describe that polypyrimidine-tract binding proteins (PTBPs), which are also typically involved in neurogenesis, are also participating in the splicing of hTERT to FL in cancer. Knockdown experiments of PTBP1 in cancer cells indicate that PTBP1 reduces hTERT FL splicing and telomerase activity. Stable knockdown of PTBP1 results in progressively shortened telomere length in H1299 and H920 lung cancer cells. RNA pulldown experiments reveal that PTBP1 interacts with hTERT pre-mRNA in a NOVA1 dependent fashion. Knockdown of PTBP1 increases the expression of PTBP2 which also interacts with NOVA1, potentially preventing the association of NOVA1 with hTERT pre-mRNA. These new data highlight that splicing in cancer cells is regulated by competition for splice sites and that combinations of splicing factors interact at cis regulatory sites on pre-mRNA transcripts. By employing hTERT as a model gene, we show the coordination of the splicing factors NOVA1 and PTBP1 in cancer by regulating telomerase that is expressed in the vast majority of cancer cell types.


Assuntos
Ribonucleoproteínas Nucleares Heterogêneas/genética , Neoplasias/genética , Proteína de Ligação a Regiões Ricas em Polipirimidinas/genética , Precursores de RNA/genética , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética , Telomerase/genética , Células A549 , Processamento Alternativo/genética , Linhagem Celular , Linhagem Celular Tumoral , Células HCT116 , Células HEK293 , Células HeLa , Humanos , Antígeno Neuro-Oncológico Ventral , Splicing de RNA/genética
10.
Nat Commun ; 9(1): 3112, 2018 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-30082712

RESUMO

Alternative splicing is dysregulated in cancer and the reactivation of telomerase involves the splicing of TERT transcripts to produce full-length (FL) TERT. Knowledge about the splicing factors that enhance or silence FL hTERT is lacking. We identified splicing factors that reduced telomerase activity and shortened telomeres using a siRNA minigene reporter screen and a lung cancer cell bioinformatics approach. A lead candidate, NOVA1, when knocked down resulted in a shift in hTERT splicing to non-catalytic isoforms, reduced telomerase activity, and progressive telomere shortening. NOVA1 knockdown also significantly altered cancer cell growth in vitro and in xenografts. Genome engineering experiments reveal that NOVA1 promotes the inclusion of exons in the reverse transcriptase domain of hTERT resulting in the production of FL hTERT transcripts. Utilizing hTERT splicing as a model splicing event in cancer may provide new insights into potentially targetable dysregulated splicing factors in cancer.


Assuntos
Processamento Alternativo , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Proteínas de Ligação a RNA/genética , Telomerase/genética , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Biologia Computacional , Deleção de Genes , Inativação Gênica , Engenharia Genética , Genoma Humano , Células HeLa , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Mutação , Transplante de Neoplasias , Antígeno Neuro-Oncológico Ventral , Fenótipo , Ligação Proteica , RNA Interferente Pequeno/metabolismo , Proteínas de Ligação a RNA/metabolismo , Telomerase/metabolismo , Telômero/ultraestrutura
11.
Nat Commun ; 8(1): 1356, 2017 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-29116081

RESUMO

Improved methods to measure the shortest (not just average) telomere lengths (TLs) are needed. We developed Telomere Shortest Length Assay (TeSLA), a technique that detects telomeres from all chromosome ends from <1 kb to 18 kb using small amounts of input DNA. TeSLA improves the specificity and efficiency of TL measurements that is facilitated by user friendly image-processing software to automatically detect and annotate band sizes, calculate average TL, as well as the percent of the shortest telomeres. Compared with other TL measurement methods, TeSLA provides more information about the shortest telomeres. The length of telomeres was measured longitudinally in peripheral blood mononuclear cells during human aging, in tissues during colon cancer progression, in telomere-related diseases such as idiopathic pulmonary fibrosis, as well as in mice and other organisms. The results indicate that TeSLA is a robust method that provides a better understanding of the shortest length of telomeres.


Assuntos
Envelhecimento/genética , Neoplasias/genética , Técnicas de Amplificação de Ácido Nucleico/métodos , Telômero/genética , Adulto , Idoso , Animais , Southern Blotting , Feminino , Células HeLa , Humanos , Processamento de Imagem Assistida por Computador , Hibridização in Situ Fluorescente/métodos , Masculino , Camundongos , Pessoa de Meia-Idade , Células NIH 3T3 , Software
12.
Sci Rep ; 7(1): 6785, 2017 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-28754961

RESUMO

Telomerase activity is not readily detected in resting human T lymphocytes, however upon antigen presentation, telomerase is transiently upregulated. Presently, it is not known if telomerase activation is necessary for the proliferation of T cells or for the maintenance of telomere lengths. In this study, we found that telomerase activation is not required for the short- term proliferation of T cells and that telomeres progressively shorten in a heterogeneous population of T cells, even if telomerase is detected. By measuring telomerase activity at the single-cell level using quantitative ddPCR techniques (ddTRAP) and by monitoring changes in the shortest telomeres with more sensitive telomere length measurement assays, we show that only a subset of CD28+ T-cells have robust telomerase activity upon stimulation and are capable of maintaining their telomere lengths during induced proliferation. The study of this T-cell subset may lead to a better understanding on how telomerase is regulated and functions in immune cells.


Assuntos
Ativação Linfocitária , Linfócitos T/imunologia , Homeostase do Telômero , Adulto , Antígenos CD28/genética , Antígenos CD28/metabolismo , Células Cultivadas , Humanos , Telomerase/metabolismo
13.
J Alzheimers Dis ; 46(3): 761-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26402514

RESUMO

BACKGROUND: Age and short leukocyte telomeres have been associated with a higher risk of Alzheimer's disease (AD). Inflammation is involved in AD and it is suggested that anti-inflammatory interleukin-10 (IL-10) may partly antagonize these processes. OBJECTIVE: The aim is to correlate telomere length (TL) in peripheral blood mononuclear cells (PBMC) from patients with AD to disease progression rate. Moreover, we evaluated whether TL was associated with IL-10 production by unstimulated or amyloid-ß (Aß)-stimulated PBMC. METHODS: We enrolled 31 late-onset AD and 20 age-matched healthy elderly (HE). After a two-year follow-up period, patients were retrospectively evaluated as slow-progressing (ADS) (Mini Mental State Examination (MMSE) decline over the two years of follow-up ≤3 points) or fast progressing AD (ADF) (MMSE decline ≥5 points). TL was measured by flow cytometry and in vitro IL-10 production by enzyme-linked immunosorbent assay. RESULTS: TL (mean±SD) for HE, ADS, and ADF was 2.3±0.1, 2.0±0.1, and 2.5±0.1 Kb, respectively. ADS showed a shorter TL compared to HE (p = 0.034) and to ADF (p = 0.005). MMSE decline correlated with TL in AD (R2 = 0.284; p = 0.008). We found a significant difference in IL-10 production between unstimulated and Aß-stimulated PBMC from ADS (40.7±13.7 versus 59.0±27.0; p = 0.004) but not from ADF (39.7±14.4 versus 42.2±22.4). HE showed a trend toward significance (47.1±25.4 versus 55.3±27.9; p = 0.10). CONCLUSION: PBMC from ADF may be characterized by an impaired response induced by Aß and by a reduced proliferative response responsible for the longer telomeres. TL might be a contributing factor in predicting the rate of AD progression.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Leucócitos Mononucleares/patologia , Telômero/genética , Telômero/patologia , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/farmacologia , Análise de Variância , Apolipoproteínas E/genética , Estudos de Casos e Controles , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Interleucina-10/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Masculino , Entrevista Psiquiátrica Padronizada , RNA Mensageiro/metabolismo
14.
J Alzheimers Dis ; 46(4): 837-42, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26402623

RESUMO

We investigated IL-10 and IL-6 production in amyloid-ß (Aß) stimulated peripheral blood mononuclear cells (PBMCs) in twenty Alzheimer's disease (AD) patients with slow progression, eleven with fast progression, and twenty age-matched controls. Promoter polymorphisms in IL-10 (position -592, -819, -1082), IL-6 (-174), transforming growth factor-ß1 (TGF-ß1) (-10, -25), interferon-γ (IFN-γ) (-874), and tumor necrosis factor-α (TNF-α) (-308) genes were analyzed. IL-10 production after Aß stimulation was high in PBMCs from slow decliners and almost completely abrogated in fast decliners. Association between AA IFN-γ low-producing genotype and fast progression was demonstrated. Investigations in a larger sample will clarify these findings.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/farmacologia , Interleucina-10/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Genótipo , Humanos , Interferon-alfa/genética , Interleucina-6/metabolismo , Masculino , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-Idade , Estatísticas não Paramétricas
15.
Exp Gerontol ; 58: 90-5, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24975295

RESUMO

Centenarians and their offspring are increasingly considered a useful model to study and characterize the mechanisms underlying healthy aging and longevity. The aim of this project is to compare the prevalence of age-related diseases and telomere length (TL), a marker of biological age and mortality, across five groups of subjects: semisupercentenarians (SSCENT) (105-109years old), centenarians (CENT) (100-104years old), centenarians' offspring (CO), age- and gender-matched offspring of parents who both died at an age in line with life expectancy (CT) and age- and gender-matched offspring of both non-long-lived parents (NLO). Information was collected on lifestyle, past and current diseases, medical history and medication use. SSCENT displayed a lower prevalence of acute myocardial infarction (p=0.027), angina (p=0.016) and depression (p=0.021) relative to CENT. CO appeared to be healthier compared to CT who, in turn, displayed a lower prevalence of both arrhythmia (p=0.034) and hypertension (p=0.046) than NLO, characterized by the lowest parental longevity. Interestingly, CO and SSCENT exhibited the longest (p<0.001) and the shortest (p<0.001) telomeres respectively while CENT showed no difference in TL compared to the younger CT and NLO. Our results strengthen the hypothesis that the longevity of parents may influence the health status of their offspring. Moreover, our data also suggest that both CENT and their offspring may be characterized by a better TL maintenance which, in turn, may contribute to their longevity and healthy aging. The observation that SSCENT showed considerable shorter telomeres compared to CENT may suggest a progressive impairment of TL maintenance mechanisms over the transition from centenarian to semisupercentenarian age.


Assuntos
Envelhecimento/genética , Leucócitos/metabolismo , Homeostase do Telômero , Telômero/genética , Fatores Etários , Idoso de 80 Anos ou mais , Envelhecimento/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Depressão/sangue , Depressão/epidemiologia , Depressão/genética , Feminino , Marcadores Genéticos , Avaliação Geriátrica , Humanos , Itália/epidemiologia , Expectativa de Vida , Longevidade/genética , Masculino , Linhagem , Prevalência , Telômero/metabolismo , Encurtamento do Telômero
16.
Biomed Res Int ; 2014: 169203, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24877062

RESUMO

The steady and dramatic increase in the incidence of Alzheimer's disease (AD) and the lack of effective treatments have stimulated the search for strategies to prevent or delay its onset and/or progression. Since the diagnosis of dementia requires a number of established features that are present when the disease is fully developed, but not always in the early stages, the need for a biological marker has proven to be urgent, in terms of both diagnosis and monitoring of AD. AD has been shown to affect peripheral blood mononuclear cells (PBMCs) that are a critical component of the immune system which provide defence against infection. Although studies are continuously supplying additional data that emphasize the central role of inflammation in AD, PBMCs have not been sufficiently investigated in this context. Delineating biochemical alterations in AD blood constituents may prove valuable in identifying accessible footprints that reflect degenerative processes within the Central Nervous System (CNS). In this review, we address the role of biomarkers in AD with a focus on the notion that PBMCs may serve as a peripheral laboratory to find molecular signatures that could aid in differential diagnosis with other forms of dementia and in monitoring of disease progression.


Assuntos
Doença de Alzheimer/sangue , Sistema Nervoso Central/metabolismo , Leucócitos Mononucleares/metabolismo , Monitorização Fisiológica/métodos , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/patologia , Biomarcadores/sangue , Sistema Nervoso Central/patologia , Diagnóstico Diferencial , Progressão da Doença , Humanos , Inflamação/sangue , Inflamação/diagnóstico , Inflamação/patologia , Leucócitos Mononucleares/patologia
17.
J Alzheimers Dis ; 40(1): 45-9, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24321892

RESUMO

The line between vascular dementia (VaD) and Alzheimer's disease (AD) is often blurred. In this study we investigated whether adenosine A2A receptor (A2AR) expression can be used to differentiate between VaD and AD. We evaluated the expression of this receptor in the peripheral blood mononuclear cells of patients with VaD, mild cognitive impairment, AD, and controls. We found statistically significant lower levels of A2AR mRNA in VaD compared to AD subjects. These data suggest that A2AR expression may help in the differential diagnosis between VaD and AD.


Assuntos
Doença de Alzheimer/patologia , Demência Vascular/patologia , Leucócitos Mononucleares/metabolismo , Receptor A2A de Adenosina/metabolismo , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/patologia , Feminino , Humanos , Masculino , RNA Mensageiro/metabolismo , Receptor A2A de Adenosina/genética
18.
J Alzheimers Dis ; 35(4): 669-74, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23478307

RESUMO

We describe a case of late onset frontotemporal dementia carrying the g.1977_1980 delCACT (Thr272fs) mutation in progranulin (GRN) gene, characterized by a positive family history for dementia and a clinical phenotype resembling dementia with Lewy bodies. Symptoms included prominent visuospatial impairment, complex misidentification syndrome, visual zooptic hallucinations, hypersomnia, mental fluctuations, and signs of parkinsonism. The patient showed normal cerebrospinal fluid levels of amyloid-ß, tau, and Ptau biomarkers, an asymmetric pattern of cerebral atrophy and hypoperfusion, and parietal hypometabolism. A major contributing factor to the diagnosis was the testing of plasmatic progranulin levels (extremely low), which prompted us to sequence GRN.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/genética , Doença por Corpos de Lewy/genética , Doença por Corpos de Lewy/patologia , Idade de Início , Idoso , Atenção/fisiologia , Códon , Função Executiva , Éxons , Feminino , Humanos , Doença por Corpos de Lewy/psicologia , Memória/fisiologia , Exame Neurológico , Testes Neuropsicológicos , Linhagem , Progranulinas , Desempenho Psicomotor/fisiologia
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