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1.
Adv Exp Med Biol ; 1233: 177-194, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32274757

RESUMO

Tauopathies are a heterogeneous group of neurodegenerative dementias involving perturbations in the levels, phosphorylation or mutations of the neuronal microtubule-binding protein Tau. Tauopathies are characterized by accumulation of hyperphosphorylated Tau leading to formation of a range of aggregates including macromolecular ensembles such as Paired Helical filaments and Neurofibrilary Tangles whose morphology characterizes and differentiates these disease states. Why nonphysiological Tau proteins elude the surveillance normal proteostatic mechanisms and eventually form these macromolecular assemblies is a central mostly unresolved question of cardinal importance for diagnoses and potential therapeutic interventions. We discuss the response of the Ubiquitin-Proteasome system, autophagy and the Endoplasmic Reticulum-Unfolded Protein response in Tauopathy models and patients, revealing interactions of components of these systems with Tau, but also of the effects of pathological Tau on these systems which eventually lead to Tau aggregation and accumulation. These interactions point to potential disease biomarkers and future potential therapeutic targets.


Assuntos
Proteostase , Tauopatias/metabolismo , Tauopatias/patologia , Demência/genética , Demência/metabolismo , Demência/patologia , Humanos , Emaranhados Neurofibrilares/genética , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Fosforilação , Complexo de Endopeptidases do Proteassoma/metabolismo , Tauopatias/genética , Ubiquitina/metabolismo , Proteínas tau/química , Proteínas tau/genética , Proteínas tau/metabolismo
2.
Nat Med ; 26(3): 387-397, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32123386

RESUMO

With the potential development of new disease-modifying Alzheimer's disease (AD) therapies, simple, widely available screening tests are needed to identify which individuals, who are experiencing symptoms of cognitive or behavioral decline, should be further evaluated for initiation of treatment. A blood-based test for AD would be a less invasive and less expensive screening tool than the currently approved cerebrospinal fluid or amyloid ß positron emission tomography (PET) diagnostic tests. We examined whether plasma tau phosphorylated at residue 181 (pTau181) could differentiate between clinically diagnosed or autopsy-confirmed AD and frontotemporal lobar degeneration. Plasma pTau181 concentrations were increased by 3.5-fold in AD compared to controls and differentiated AD from both clinically diagnosed (receiver operating characteristic area under the curve of 0.894) and autopsy-confirmed frontotemporal lobar degeneration (area under the curve of 0.878). Plasma pTau181 identified individuals who were amyloid ß-PET-positive regardless of clinical diagnosis and correlated with cortical tau protein deposition measured by 18F-flortaucipir PET. Plasma pTau181 may be useful to screen for tau pathology associated with AD.


Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico , Degeneração Lobar Frontotemporal/sangue , Degeneração Lobar Frontotemporal/diagnóstico , Proteínas tau/sangue , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Amiloide/metabolismo , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Cognição , Feminino , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/patologia , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Proteínas de Neurofilamentos/sangue , Fosforilação , Tomografia por Emissão de Pósitrons , Índice de Gravidade de Doença , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/genética
3.
Phys Chem Chem Phys ; 22(14): 7241-7249, 2020 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-32207466

RESUMO

The self-assembly of Tau protein into amyloid structures is associated with Alzheimer's disease and other tauopathies. Dominant familial mutations in the Tau gene, such as P301L and P301S, increase the propensity of the Tau protein to aggregate abnormally into filaments. A quantitative description of the fibrillization process of Tau will facilitate the understanding of the cytotoxicity of Tau aggregates and their intercellular spreading. Here, we investigated the aggregation kinetics of Tau and disease-associated P301L and P301S mutants by combined thioflavin T assay and kinetic modeling, which revealed the rate constants of individual microscopic steps in the process of amyloid formation. Compared to WT Tau, P301L shows a larger primary nucleation rate while P301S has higher elongation and fragmentation rates and a more apparent fibril annealing process. Cross-seeding assays and FRET experiments indicate that the structures of the fibrillar nuclei of the three variants are distinct. These results provide detailed insights into how the amyloid aggregation mechanism of Tau protein is affected by the familial mutations P301L and P301S, and relates the physical properties of Tau mutants to their pathogenic mechanism.


Assuntos
Agregação Patológica de Proteínas/fisiopatologia , Proteínas tau/química , Proteínas tau/genética , Doença de Alzheimer/fisiopatologia , Transferência Ressonante de Energia de Fluorescência , Humanos , Cinética , Mutação , Proteínas tau/toxicidade , Proteínas tau/ultraestrutura
4.
Nat Rev Neurol ; 16(4): 213-228, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32203398

RESUMO

Frontotemporal dementia (FTD) encompasses a spectrum of clinical syndromes characterized by progressive executive, behavioural and language dysfunction. The various FTD spectrum disorders are associated with brain accumulation of different proteins: tau, the transactive response DNA binding protein of 43 kDa (TDP43), or fused in sarcoma (FUS) protein, Ewing sarcoma protein and TATA-binding protein-associated factor 15 (TAF15) (collectively known as FET proteins). Approximately 60% of patients with FTD have autosomal dominant mutations in C9orf72, GRN or MAPT genes. Currently available treatments are symptomatic and provide limited benefit. However, the increased understanding of FTD pathogenesis is driving the development of potential disease-modifying therapies. Most of these drugs target pathological tau - this category includes tau phosphorylation inhibitors, tau aggregation inhibitors, active and passive anti-tau immunotherapies, and MAPT-targeted antisense oligonucleotides. Some of these therapeutic approaches are being tested in phase II clinical trials. Pharmacological approaches that target the effects of GRN and C9orf72 mutations are also in development. Key results of large clinical trials will be available in a few years. However, clinical trials in FTD pose several challenges, and the development of specific brain imaging and molecular biomarkers could facilitate the recruitment of clinically homogenous groups to improve the chances of positive clinical trial results.


Assuntos
Anticorpos/uso terapêutico , Afasia Primária Progressiva/tratamento farmacológico , Desenvolvimento de Medicamentos , Demência Frontotemporal/tratamento farmacológico , Moduladores de Tubulina/uso terapêutico , Esclerose Amiotrófica Lateral/tratamento farmacológico , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Afasia Primária Progressiva/genética , Afasia Primária Progressiva/metabolismo , Proteína C9orf72/genética , Proteínas de Ligação a DNA/metabolismo , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Humanos , Imunização Passiva , Imunoterapia Ativa , Terapia de Alvo Molecular , Progranulinas/genética , Proteína EWS de Ligação a RNA/metabolismo , Proteína FUS de Ligação a RNA/metabolismo , Paralisia Supranuclear Progressiva/tratamento farmacológico , Paralisia Supranuclear Progressiva/genética , Paralisia Supranuclear Progressiva/metabolismo , Fatores Associados à Proteína de Ligação a TATA/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismo
5.
J Agric Food Chem ; 68(7): 2054-2062, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-31995984

RESUMO

Alzheimer's disease (AD) is a common neurodegenerative disease which is partly characterized by the aggregation of hyperphosphorylated Tau proteins forming neurofibrillary tangles that promote AD pathogenesis. In this study, we investigated the effects of tanshinone IIA (Tan IIA) isolated from Salvia miltiorrhiza on Tau degradation in the treatment of AD. The results showed that Tan IIA reduced the Tau expression and attenuated Tau phosphorylation in N2a cells, Tau-overexpressing cells, and 3×Tg-AD mouse primary neuron cells. Moreover, Tan IIA increased polyubiquitinated Tau accumulation and induced proteasomal degradation of the Tau protein. Additionally, Tan IIA became bound to the Tau protein and inhibited the formation of heparin-induced Tau fibrils. In summary, Tan IIA can increase polyubiquitinated Tau accumulation and induce the proteasomal degradation of the Tau protein and the binding of Tan IIA to the Tau protein, inhibiting the formation of Tau fibrils. Tan IIA may be further explored as a potential candidate for AD treatment.


Assuntos
Abietanos/farmacologia , Doença de Alzheimer/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Salvia miltiorrhiza/química , Ubiquitinas/metabolismo , Proteínas tau/química , Proteínas tau/metabolismo , Doença de Alzheimer/genética , Animais , Linhagem Celular , Humanos , Camundongos , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , Proteólise/efeitos dos fármacos , Proteínas tau/genética
6.
Proc Natl Acad Sci U S A ; 117(6): 2923-2929, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-31974309

RESUMO

Small heat shock proteins (sHSPs) are a class of ATP-independent molecular chaperones that play vital roles in maintaining protein solubility and preventing aberrant protein aggregation. They form highly dynamic, polydisperse oligomeric ensembles and contain long intrinsically disordered regions. Experimental challenges posed by these properties have greatly impeded our understanding of sHSP structure and mechanism of action. Here we characterize interactions between the human sHSP HspB1 (Hsp27) and microtubule-associated protein tau, which is implicated in multiple dementias, including Alzheimer's disease. We show that tau binds both to a well-known binding groove within the structured alpha-crystallin domain (ACD) and to sites within the enigmatic, disordered N-terminal region (NTR) of HspB1. However, only interactions involving the NTR lead to productive chaperone activity, whereas ACD binding is uncorrelated with chaperone function. The tau-binding groove in the ACD also binds short hydrophobic regions within HspB1 itself, and HspB1 mutations that disrupt these intrinsic ACD-NTR interactions greatly enhance chaperone activity toward tau. This leads to a mechanism in which the release of the disordered NTR from a binding groove on the ACD enhances chaperone activity toward tau. The study advances understanding of the mechanisms by which sHSPs achieve their chaperone activity against amyloid-forming clients and how cells defend against pathological tau aggregation. Furthermore, the resulting mechanistic model points to ways in which sHSP chaperone activity may be increased, either by native factors within the cell or by therapeutic intervention.


Assuntos
Proteínas de Choque Térmico/química , Proteínas de Choque Térmico/metabolismo , Chaperonas Moleculares/química , Chaperonas Moleculares/metabolismo , Proteínas tau/metabolismo , Proteínas de Choque Térmico/genética , Humanos , Modelos Moleculares , Chaperonas Moleculares/genética , Ligação Proteica , Domínios Proteicos , alfa-Cristalinas/metabolismo , Proteínas tau/genética
7.
Nat Commun ; 11(1): 571, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996674

RESUMO

Aggregation of the Tau protein into fibrils defines progression of neurodegenerative diseases, including Alzheimer's Disease. The molecular basis for potentially toxic reactions of Tau aggregates is poorly understood. Here we show that π-stacking by Arginine side-chains drives protein binding to Tau fibrils. We mapped an aggregation-dependent interaction pattern of Tau. Fibrils recruit specifically aberrant interactors characterised by intrinsically disordered regions of atypical sequence features. Arginine residues are key to initiate these aberrant interactions. Crucial for scavenging is the guanidinium group of its side chain, not its charge, indicating a key role of π-stacking chemistry for driving aberrant fibril interactions. Remarkably, despite the non-hydrophobic interaction mode, the molecular chaperone Hsp90 can modulate aberrant fibril binding. Together, our data present a molecular mode of action for derailment of protein-protein interaction by neurotoxic fibrils.


Assuntos
Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Arginina/metabolismo , Ligação Proteica , Proteínas tau/metabolismo , Doença de Alzheimer/genética , Sequência de Aminoácidos , Animais , Arginina/química , Progressão da Doença , Guanidina/metabolismo , Proteínas de Choque Térmico HSP90 , Humanos , Espectrometria de Massas , Chaperonas Moleculares , Agregados Proteicos , Domínios Proteicos , Dobramento de Proteína , Proteoma , Ratos , Análise de Sequência de Proteína , Proteínas tau/química , Proteínas tau/genética
8.
Nat Commun ; 11(1): 7, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31911587

RESUMO

The deposition of pathological tau is a common feature in several neurodegenerative tauopathies. Although equal ratios of tau isoforms with 3 (3R) and 4 (4R) microtubule-binding repeats are expressed in the adult human brain, the pathological tau from different tauopathies have distinct isoform compositions and cell type specificities. The underlying mechanisms of tauopathies are unknown, partially due to the lack of proper models. Here, we generate a new transgenic mouse line expressing equal ratios of 3R and 4R human tau isoforms (6hTau mice). Intracerebral injections of distinct human tauopathy brain-derived tau strains into 6hTau mice recapitulate the deposition of pathological tau with distinct tau isoform compositions and cell type specificities as in human tauopathies. Moreover, through in vivo propagation of these tau strains among different mouse lines, we demonstrate that the transmission of distinct tau strains is independent of strain isoform compositions, but instead intrinsic to unique pathological conformations.


Assuntos
Isoformas de Proteínas/metabolismo , Tauopatias/metabolismo , Proteínas tau/metabolismo , Animais , Encéfalo/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Isoformas de Proteínas/genética , Tauopatias/genética , Proteínas tau/genética
9.
Toxicol Lett ; 319: 213-224, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31783120

RESUMO

The upregulated α-synuclein (α-syn) and Tau co-occur in methamphetamine (METH) abusers' brains. Here, we designed experiments mainly to investigate whether α-syn and Tau interact in METH exposure. We detected the expression of α-syn, total Tau, and phosphorylation of Tau at Serine 396 (pSer396 Tau) under in vitro and in vivo conditions after METH exposure to determine the co-occurrence of α-syn and Tau. We also explored the effect of α-syn or Tau on one another by silencing and knocking-out one of them in METH treatment. We found that METH increased the α-syn, total Tau, and pSer396 Tau protein level in SH-SY5Y cells, primary cultured neurons, and in mice brains. In additional, reducing α-syn level can relieve and even normalize the pSer396 Tau and total Tau overexpression after treatment of METH. Furthermore, knocking out Tau can effectively inhibit METH induced overexpression of α-syn in mice brains. Finally, knocking out α-syn or Tau can effectively reduce METH-induced neurotoxicity in mice brains. This research could provide potential therapeutic approaches targeting the vicious circle between α-syn and Tau in METH abusers and patients with neurodegenerative disorders.


Assuntos
Estimulantes do Sistema Nervoso Central/toxicidade , Metanfetamina/toxicidade , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , alfa-Sinucleína/biossíntese , Proteínas tau/biossíntese , Animais , Comportamento Animal/efeitos dos fármacos , Linhagem Celular , Inativação Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Síndromes Neurotóxicas/psicologia , Cultura Primária de Células , RNA Interferente Pequeno , alfa-Sinucleína/genética , Proteínas tau/genética , Proteínas tau/metabolismo
10.
Neurology ; 93(18): e1699-e1706, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31578297

RESUMO

OBJECTIVE: To characterize the time course of ventricular volume expansion in genetic frontotemporal dementia (FTD) and identify the onset time and rates of ventricular expansion in presymptomatic FTD mutation carriers. METHODS: Participants included patients with a mutation in MAPT, PGRN, or C9orf72, or first-degree relatives of mutation carriers from the GENFI study with MRI scans at study baseline and at 1 year follow-up. Ventricular volumes were obtained from MRI scans using FreeSurfer, with manual editing of segmentation and comparison to fully automated segmentation to establish reliability. Linear mixed models were used to identify differences in ventricular volume and in expansion rates as a function of time to expected disease onset between presymptomatic carriers and noncarriers. RESULTS: A total of 123 participants met the inclusion criteria and were included in the analysis (18 symptomatic carriers, 46 presymptomatic mutation carriers, and 56 noncarriers). Ventricular volume differences were observed 4 years prior to symptom disease onset for presymptomatic carriers compared to noncarriers. Annualized rates of ventricular volume expansion were greater in presymptomatic carriers relative to noncarriers. Importantly, time-intensive manually edited and fully automated ventricular volume resulted in similar findings. CONCLUSIONS: Ventricular volume differences are detectable in presymptomatic genetic FTD. Concordance of results from time-intensive manual editing and fully automatic segmentation approaches support its value as a measure of disease onset and progression in future studies in both presymptomatic and symptomatic genetic FTD.


Assuntos
Ventrículos Cerebrais/diagnóstico por imagem , Demência Frontotemporal/diagnóstico por imagem , Sintomas Prodrômicos , Adulto , Idoso , Proteína C9orf72/genética , Ventrículos Cerebrais/patologia , Feminino , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Heterozigoto , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Progranulinas/genética , Proteínas tau/genética
11.
Neurology ; 93(18): e1707-e1714, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31537715

RESUMO

OBJECTIVE: To determine autosomal dominant genetic predictors of survival in individuals with behavioral variant frontotemporal degeneration (bvFTD). METHODS: A retrospective chart review of 174 cases with a clinical phenotype of bvFTD but no associated elementary neurologic features was performed, with diagnosis either autopsy-confirmed (n = 57) or supported by CSF evidence of non-Alzheimer pathology (n = 117). Genetic analysis of the 3 most common genes with pathogenic autosomal dominant mutations associated with frontotemporal degeneration was performed in all patients, which identified cases with C9orf72 expansion (n = 28), progranulin (GRN) mutation (n = 12), and microtubule-associated protein tau (MAPT) mutation (n = 10). Cox proportional hazards regressions were used to test for associations between survival and mutation status, sex, age at symptom onset, and education. RESULTS: Across all patients with bvFTD, the presence of a disease-associated pathogenic mutation was associated with shortened survival (hazard ratio [HR] 2.164, 95% confidence interval [CI] 1.391, 3.368). In separate models, a GRN mutation (HR 2.423, 95% CI 1.237, 4.744), MAPT mutation (HR 8.056, 95% CI 2.938, 22.092), and C9orf72 expansion (HR 1.832, 95% CI 1.034, 3.244) were each individually associated with shorter survival relative to sporadic bvFTD. A mutation on the MAPT gene results in an earlier age at onset than a C9orf72 expansion or mutation on the GRN gene (p = 0.016). CONCLUSIONS: Our findings suggest that autosomal dominantly inherited mutations, modulated by age at symptom onset, associate with shorter survival among patients with bvFTD. We suggest that clinical trials and clinical management should consider mutation status and age at onset when evaluating disease progression.


Assuntos
Demência Frontotemporal/mortalidade , Taxa de Sobrevida , Idade de Início , Idoso , Proteína C9orf72/genética , Feminino , Demência Frontotemporal/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Prognóstico , Progranulinas/genética , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Proteínas tau/genética
12.
Molecules ; 24(16)2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31434312

RESUMO

Alternative splicing of tau pre-mRNA is regulated by a 5' splice site (5'ss) hairpin present at the exon 10-intron 10 junction. Single mutations within the hairpin sequence alter hairpin structural stability and/or the binding of splicing factors, resulting in disease-causing aberrant splicing of exon 10. The hairpin structure contains about seven stably formed base pairs and thus may be suitable for targeting through antisense strands. Here, we used antisense peptide nucleic acids (asPNAs) to probe and target the tau pre-mRNA exon 10 5'ss hairpin structure through strand invasion. We characterized by electrophoretic mobility shift assay the binding of the designed asPNAs to model tau splice site hairpins. The relatively short (10-15 mer) asPNAs showed nanomolar binding to wild-type hairpins as well as a disease-causing mutant hairpin C+19G, albeit with reduced binding strength. Thus, the structural stabilizing effect of C+19G mutation could be revealed by asPNA binding. In addition, our cell culture minigene splicing assay data revealed that application of an asPNA targeting the 3' arm of the hairpin resulted in an increased exon 10 inclusion level for the disease-associated mutant C+19G, probably by exposing the 5'ss as well as inhibiting the binding of protein factors to the intronic spicing silencer. On the contrary, the application of asPNAs targeting the 5' arm of the hairpin caused an increased exon 10 exclusion for a disease-associated mutant C+14U, mainly by blocking the 5'ss. PNAs could enter cells through conjugation with amino sugar neamine or by cotransfection with minigene plasmids using a commercially available transfection reagent.


Assuntos
Processamento Alternativo , Oligonucleotídeos Antissenso/genética , Ácidos Nucleicos Peptídicos/genética , Proteínas tau/genética , Éxons , Células HEK293 , Humanos , Conformação Molecular , Precursores de RNA , Sítios de Splice de RNA , RNA Mensageiro/genética
13.
J Korean Med Sci ; 34(33): e225, 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31436053

RESUMO

BACKGROUND: Tauopathies, a class of neurodegenerative diseases that includes Alzheimer's disease (AD), are characterized by the deposition of neurofibrillary tangles composed of hyperphosphorylated tau protein in the human brain. As abnormal alterations in histone acetylation and methylation show a cause and effect relationship with AD, we investigated the role of several Jumonji domain-containing histone demethylase (JHDM) genes, which have yet to be studied in AD pathology. METHODS: To examine alterations of several JHDM genes in AD pathology, we performed bioinformatics analyses of JHDM gene expression profiles in brain tissue samples from deceased AD patients. Furthermore, to investigate the possible relationship between alterations in JHDM gene expression profiles and AD pathology in vivo, we examined whether tissue-specific downregulation of JHDM Drosophila homologs (kdm) can affect tauR406W-induced neurotoxicity using transgenic flies containing the UAS-Gal4 binary system. RESULTS: The expression levels of JHDM1A, JHDM2A/2B, and JHDM3A/3B were significantly higher in postmortem brain tissue from patients with AD than from non-demented controls, whereas JHDM1B mRNA levels were downregulated in the brains of patients with AD. Using transgenic flies, we revealed that knockdown of kdm2 (homolog to human JHDM1), kdm3 (homolog to human JHDM2), kdm4a (homolog to human JHDM3A), or kdm4b (homolog to human JHDM3B) genes in the eye ameliorated the tauR406W-engendered defects, resulting in less severe phenotypes. However, kdm4a knockdown in the central nervous system uniquely ameliorated tauR406W-induced locomotion defects by restoring heterochromatin. CONCLUSION: Our results suggest that downregulation of kdm4a expression may be a potential therapeutic target in AD.


Assuntos
Proteínas de Drosophila/genética , Histona Desmetilases/metabolismo , Proteínas tau/genética , Idoso , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Animais Geneticamente Modificados/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Proteínas de Drosophila/antagonistas & inibidores , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Feminino , Heterocromatina/metabolismo , Histona Desmetilases/antagonistas & inibidores , Histona Desmetilases/genética , Humanos , Locomoção , Masculino , Pessoa de Meia-Idade , Mutagênese Sítio-Dirigida , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Interferência de RNA , Transcriptoma , Proteínas tau/metabolismo
14.
Biomed Res Int ; 2019: 9573248, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467920

RESUMO

The neonatal immune system is still immature, which makes it more susceptible to the infectious agents. Neonatal immune activation is associated with increased permeability of the blood-brain barrier, causing an inflammatory cascade in the CNS and altering behavioral and neurochemical parameters. One of the hypotheses that has been studied is that neuroinflammation may be involved in neurodegenerative processes, such as Alzheimer's disease (AD). We evaluate visuospatial memory, cytokines levels, and the expression of tau and GSK-3ß proteins in hippocampus and cortex of animals exposed to neonatal endotoxemia. C57BL/6 mice aging two days received a single injection of subcutaneous lipopolysaccharide (LPS). At 60,120, and 180 days of age, visual-spatial memory was evaluated and the hippocampus and cortex were dissected to evaluate the cytokines levels and expression of tau and GSK-3ß proteins. The animals exposed to LPS in the neonatal period present with visuospatial memory impairment at 120 and 180 days of age. Here there was an increase of TNF-α and IL-1ß levels in the hippocampus and cortex only at 60 days of age. Here there was an increase in the expression of GSK-3ß in hippocampus of the animals at 60, 120, and 180 days of age. In the cortex, this increase occurred in the 120 and 180 days of age. Tau protein expression was high in hippocampus and cortex at 120 days of age and in hippocampus at 180 days of age. The data observed show that neonatal immune activation may be associated with visuospatial memory impairment, neuroinflammation, and increased expression of GSK-3ß and Tau proteins in the long term.


Assuntos
Animais Recém-Nascidos/imunologia , Encéfalo/imunologia , Endotoxemia/imunologia , Inflamação/imunologia , Animais , Animais Recém-Nascidos/genética , Barreira Hematoencefálica/imunologia , Encéfalo/crescimento & desenvolvimento , Córtex Cerebelar/imunologia , Endotoxemia/induzido quimicamente , Glicogênio Sintase Quinase 3 beta/genética , Hipocampo/imunologia , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , Lipopolissacarídeos/toxicidade , Camundongos , Proteínas tau/genética
15.
PLoS One ; 14(7): e0217384, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31260447

RESUMO

[18F]T807 is a potent tau protein imaging agent. In order to fulfill the demand from preclinical and clinical studies, we developed an automated one-pot two-step synthesis of this potent tau imaging agent and studied its stability, and dosimetry in mice and monkeys. We also conducted a preliminary study of this imaging agent in humans. Using this one-pot two-step method, the radiochemical yield (RCY) of [18F]T807 was 20.5 ± 6.1% (n = 15) at the end of bombardment (EOB) in a synthesis time of 70±5 min. The chemical and radiochemical purities were >90% and the specific activities were 151 ± 52 GBq/µmol. The quality of [18F]T807 synthesized by this method met the U.S. Pharmacopoeia (USP) criteria. The stability test showed that the [18F]T807 injection was stable at room temperature for up to 4 h after the end of synthesis (EOS). The estimated effective dose of the [18F]T807 injection extrapolated from monkeys was 19 µSv/MBq (n = 2), while the estimated effective doses of the [18F]T807 injection extrapolated from fasted and non-fasted mice were 123 ± 27 (n = 3) and 94 ± 19 (n = 4) µSv/MBq, respectively. This one-pot two-step automated method produced the [18F]T807 injection with high reproducibility and high quality. PET imaging and radiation dosimetry evaluation in mice and Formosan rock monkeys suggested that the [18F]T807 injection synthesized by this method is suitable for use in human PET imaging studies. Thus, this method could fulfill the demand for the [18F]T807 injection in both preclinical and clinical studies of tauopathies, especially for nearby study sites without cyclotrons.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Carbolinas/síntese química , Meios de Contraste/síntese química , Compostos Radiofarmacêuticos/síntese química , Proteínas tau/química , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Disponibilidade Biológica , Carbolinas/sangue , Carbolinas/farmacocinética , Meios de Contraste/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Expressão Gênica , Haplorrinos , Humanos , Injeções Intravenosas , Macaca , Masculino , Camundongos , Camundongos Endogâmicos ICR , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos , Radiometria , Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Tecidual , Proteínas tau/genética
16.
J Toxicol Sci ; 44(7): 493-503, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31270305

RESUMO

Methamphetamine (METH) is a potent and highly addictive central nervous system stimulant. The association between METH exposure and Alzheimer's disease (AD) has gained more attention, but, the mechanisms behind METH-induced neuron-related adverse outcomes remain poorly understood. With the western blot assay, our results revealed that METH exposure significantly increased the expression of AD-associated pathological proteins, including the amyloid precursor protein (APP) and the phosphorylated tau protein (p-tau). Meanwhile, the insulin signaling was disturbed after the administration of METH, since the key insulin signaling proteins, such as p-AKT, p-GSK3α, p-GSK3ß and p-ERK, were reduced. Additionally, the linking between the pathological proteins and the insulin signaling mediated by METH in the present work was verified by the treatment with the insulin signaling enhancer rosiglitazone, which was shown to improve the insulin signaling and decrease APP and p-tau expression. Thus, targeting insulin signaling may provide novel insights into potential therapeutic intervention for METH-mediated AD-like neurodegeneration.


Assuntos
Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Estimulantes do Sistema Nervoso Central/efeitos adversos , Expressão Gênica , Insulina/fisiologia , Metanfetamina/efeitos adversos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Proteínas tau/genética , Proteínas tau/metabolismo , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/genética , Linhagem Celular Tumoral , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Quinase 3 da Glicogênio Sintase/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/fisiologia
17.
J Agric Food Chem ; 67(30): 8348-8360, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31304751

RESUMO

We have recently demonstrated that tau hyperphosphorylation causes diabetic synaptic neurodegeneration of retinal ganglion cells (RGCs), which might be the earliest affair during the pathogenesis of diabetic retinopathy (DR). Thus, there is a pressing need to seek therapeutic agents possessing neuroprotective effects against tau hyperphosphorylation in RGCs for arresting the progression of DR. Here, using a well-characterized diabetes model of db/db mouse, we discovered that topical ocular application of 10 mg/kg/day of ginsenoside Rg1 (GRg1), one of the major active ingredients extracted from Panax ginseng and Panax notoginseng, ameliorated hyperphosphorylated tau-triggered RGCs synaptic neurodegeneration in diabetic mice. The neuroprotective effects of GRg1 on diabetic retinae were abrogated when retinal IRS-1 or Akt was suppressed by intravitreal injection with si-IRS-1 or topically coadministered with a specific inhibitor of Akt, respectively. However, selective repression of retinal GSK3ß by intravitreal administration of si-GSK3ß rescued the neuroprotective properties of GRg1 when Akt was inactivated. Therefore, the present study showed for the first time that GRg1 can prevent hyperphosphorylated tau-induced synaptic neurodegeneration of RGCs via activation of IRS-1/Akt/GSK3ß signaling in the early phase of DR. Moreover, our data clarify the potential therapeutic significance of GRg1 for neuroprotective intervention strategies of DR.


Assuntos
Retinopatia Diabética/tratamento farmacológico , Ginsenosídeos/administração & dosagem , Glicogênio Sintase Quinase 3 beta/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células Ganglionares da Retina/efeitos dos fármacos , Proteínas tau/metabolismo , Animais , Retinopatia Diabética/genética , Retinopatia Diabética/metabolismo , Glicogênio Sintase Quinase 3 beta/genética , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Degeneração Neural/tratamento farmacológico , Degeneração Neural/genética , Degeneração Neural/metabolismo , Panax notoginseng/química , Fosforilação , Extratos Vegetais/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/genética , Retina/patologia , Células Ganglionares da Retina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas tau/genética
18.
Neurology ; 93(8): e758-e765, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31315971

RESUMO

OBJECTIVE: To determine the frontal lobe proton magnetic resonance spectroscopy (1H MRS) abnormalities in asymptomatic and symptomatic carriers of microtubule-associated protein tau (MAPT) mutations. METHODS: We recruited patients with MAPT mutations from 5 individual families, who underwent single voxel 1H MRS from the medial frontal lobe at 3T (n = 19) from the Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Study at the Mayo Clinic site. Asymptomatic MAPT mutation carriers (n = 9) had Frontotemporal Lobar Degeneration Clinical Dementia Rating Sum of Boxes (FTLD-CDR SOB) score of zero, and symptomatic MAPT mutation carriers (n = 10) had a median FTLD-CDR SOB score of 5. Noncarriers from healthy first-degree relatives of the patients were recruited as controls (n = 25). The demographic aspects and 1H MRS metabolite ratios were compared by use of the Fisher exact test for sex and linear mixed models to account for within-family correlations. We used Tukey contrasts for pair-wise comparisons. RESULTS: Asymptomatic MAPT mutation carriers had lower neuronal marker N-acetylaspartate (NAA)/creatine (Cr) (p = 0.001) and lower NAA/myo-inositol (mI) (p = 0.026) than noncarriers after adjustment for age. Symptomatic MAPT mutation carriers had lower NAA/Cr (p = 0.01) and NAA/mI (p = 0.01) and higher mI/Cr (p = 0.02) compared to noncarriers after adjustment for age. Furthermore, NAA/Cr (p = 0.006) and NAA/mI (p < 0.001) ratios decreased, accompanied by an increase in mI/Cr ratio (p = 0.001), as the ages of carriers approached and passed the age at symptom onset. CONCLUSION: Frontal lobe neurochemical alterations measured with 1H MRS precede the symptom onset in MAPT mutation carriers. Frontal lobe 1H MRS is a potential biomarker for early neurodegenerative processes in MAPT mutation carriers.


Assuntos
Ácido Aspártico/análogos & derivados , Creatina/metabolismo , Demência/metabolismo , Lobo Frontal/metabolismo , Degeneração Lobar Frontotemporal/metabolismo , Inositol/metabolismo , Proteínas tau/metabolismo , Adulto , Ácido Aspártico/metabolismo , Doenças Assintomáticas , Biomarcadores/metabolismo , Estudos de Casos e Controles , Demência/complicações , Demência/genética , Feminino , Degeneração Lobar Frontotemporal/complicações , Degeneração Lobar Frontotemporal/diagnóstico , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Espectroscopia de Prótons por Ressonância Magnética , Adulto Jovem , Proteínas tau/genética
19.
PLoS One ; 14(7): e0219210, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31291322

RESUMO

Tauopathies are neurodegenerative diseases that affect millions of people worldwide including those with Alzheimer's disease. While many efforts have focused on understanding the role of tau protein in neurodegeneration, there has been little done to systematically analyze and study the structures within tau's encoding RNA and their connection to disease pathology. Knowledge of RNA structure can provide insights into disease mechanisms and how to affect protein production for therapeutic benefit. Using computational methods based on thermodynamic stability and evolutionary conservation, we identified structures throughout the tau pre-mRNA, especially at exon-intron junctions and within the 5' and 3' untranslated regions (UTRs). In particular, structures were identified at twenty exon-intron junctions. The 5' UTR contains one structured region, which lies within a known internal ribosome entry site. The 3' UTR contains eight structured regions, including one that contains a polyadenylation signal. A series of functional experiments were carried out to assess the effects of mutations associated with mis-regulation of alternative splicing of exon 10 and to identify regions of the 3' UTR that contain cis-regulatory elements. These studies defined novel structural regions within the mRNA that affect stability and pre-mRNA splicing and may lead to new therapeutic targets for treating tau-associated diseases.


Assuntos
Precursores de RNA/química , RNA Mensageiro/genética , Tauopatias/genética , Proteínas tau/genética , Regiões 3' não Traduzidas/genética , Processamento Alternativo/genética , Doença de Alzheimer , Éxons/genética , Humanos , Íntrons/genética , Mutação , Conformação de Ácido Nucleico , Poliadenilação/genética , Precursores de RNA/genética , RNA Mensageiro/química , Tauopatias/patologia , Proteínas tau/química
20.
EMBO J ; 38(13): e101174, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31268600

RESUMO

Tau is a scaffolding protein that serves multiple cellular functions that are perturbed in neurodegenerative diseases, including Alzheimer's disease (AD) and frontotemporal dementia (FTD). We have recently shown that amyloid-ß, the second hallmark of AD, induces de novo protein synthesis of tau. Importantly, this activation was found to be tau-dependent, raising the question of whether FTD-tau by itself affects protein synthesis. We therefore applied non-canonical amino acid labelling to visualise and identify newly synthesised proteins in the K369I tau transgenic K3 mouse model of FTD. This revealed massively decreased protein synthesis in neurons containing pathologically phosphorylated tau, a finding confirmed in P301L mutant tau transgenic rTg4510 mice. Using quantitative SWATH-MS proteomics, we identified changes in 247 proteins of the de novo proteome of K3 mice. These included decreased synthesis of the ribosomal proteins RPL23, RPLP0, RPL19 and RPS16, a finding that was validated in both K3 and rTg4510 mice. Together, our findings present a potential pathomechanism by which pathological tau interferes with cellular functions through the dysregulation of ribosomal protein synthesis.


Assuntos
Aminoácidos/metabolismo , Demência Frontotemporal/genética , Proteômica/métodos , Proteínas Ribossômicas/metabolismo , Proteínas tau/genética , Animais , Modelos Animais de Doenças , Demência Frontotemporal/metabolismo , Regulação da Expressão Gênica , Células HEK293 , Humanos , Camundongos , Camundongos Transgênicos , Mutação , Neurônios/metabolismo , Fosforilação , Coloração e Rotulagem , Proteínas tau/metabolismo
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