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1.
Invest Ophthalmol Vis Sci ; 60(6): 2380-2387, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31141609

RESUMO

Purpose: To determine whether tauopathies are associated with impaired autophagy and involved in the death of retinal ganglion cells (RGCs) of rats from an optic nerve crush (ONC). Methods: Short interfering RNA (siRNA) of the tau gene (si-Tau) or nontargeting siRNA (si-NC) was injected intravitreally 48 hours prior to ONC. The effects of silencing the tau gene on neuroprotection were determined by the number of Tuj-1-stained RGCs on days 7 and 14 after the ONC. The changes in the expressions of phosphorylated tau, P62, and LC3B were determined by immunoblots and immunohistochemistry on day 7. Results: Autophagy was impaired in the retina on day 7 after the ONC as the P62 level increased by 3.1-fold from the sham control level with a reduction in the ratio LC3B2/LC3B1. There was a 2.1-fold increase of phosphorylated tau (ser 396) in the retina, and si-Tau depressed the increase by 1.3-fold (n = 3 each). The expressions of tau and P62 were well colocalized. They were observed in the somas of RGCs and retinal nerve fibers (RNFs), and these expressions were increased after the ONC. Pretreatment by si-Tau showed significant protection in the number of RGCs after the ONC. Specifically, the density of RGCs was 540 ± 74.5 cells/mm2 on day 14 in the si-NC group, while the level was maintained at 1321 ± 192 cells/mm2 in the si-Tau group (n = 4 each). Conclusions: Silencing the tau gene is neuroprotective, and tauopathies may be involved in the death of RGCs after ONC. Impaired autophagy may be involved in ONC-induced tauopathies.


Assuntos
Autofagia/fisiologia , Compressão Nervosa , Neuroproteção/fisiologia , Traumatismos do Nervo Óptico/fisiopatologia , Células Ganglionares da Retina/fisiologia , Proteínas tau/fisiologia , Animais , Sobrevivência Celular/fisiologia , Modelos Animais de Doenças , Inativação Gênica , Masculino , Ratos , Proteínas tau/metabolismo
2.
Neurosci Lett ; 705: 183-194, 2019 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-31028844

RESUMO

Alzheimer's disease (AD) is characterized by two major pathological lesions in the brain, amyloid plaques and neurofibrillary tangles (NFTs) composed mainly of amyloid-ß (Aß) peptides and hyperphosphorylated tau, respectively. Although accumulation of toxic Aß species in the brain has been proposed as one of the important early events in AD, continued lack of success of clinical trials based on Aß-targeting drugs has triggered the field to seek out alternative disease mechanisms and related therapeutic strategies. One of the new approaches is to uncover novel roles of pathological tau during disease progression. This review will primarily focus on recent advances in understanding the contributions of tau to AD.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Proteínas tau/metabolismo , Proteínas tau/fisiologia , Doença de Alzheimer/complicações , Humanos , Inflamação/complicações , Inflamação/fisiopatologia , Transmissão Sináptica/fisiologia
3.
Proc Natl Acad Sci U S A ; 116(12): 5765-5774, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30842285

RESUMO

Mutations in the vacuolar protein sorting 35 ortholog (VPS35) gene represent a cause of late-onset, autosomal dominant familial Parkinson's disease (PD). A single missense mutation, D620N, is considered pathogenic based upon its segregation with disease in multiple families with PD. At present, the mechanism(s) by which familial VPS35 mutations precipitate neurodegeneration in PD are poorly understood. Here, we employ a germline D620N VPS35 knockin (KI) mouse model of PD to formally establish the age-related pathogenic effects of the D620N mutation at physiological expression levels. Our data demonstrate that a heterozygous or homozygous D620N mutation is sufficient to reproduce key neuropathological hallmarks of PD as indicated by the progressive degeneration of nigrostriatal pathway dopaminergic neurons and widespread axonal pathology. Unexpectedly, endogenous D620N VPS35 expression induces robust tau-positive somatodendritic pathology throughout the brain as indicated by abnormal hyperphosphorylated and conformation-specific tau, which may represent an important and early feature of mutant VPS35-induced neurodegeneration in PD. In contrast, we find no evidence for α-synuclein-positive neuropathology in aged VPS35 KI mice, a hallmark of Lewy body pathology in PD. D620N VPS35 expression also fails to modify the lethal neurodegenerative phenotype of human A53T-α-synuclein transgenic mice. Finally, by crossing VPS35 KI and null mice, our data demonstrate that a single D620N VPS35 allele is sufficient for survival and early maintenance of dopaminergic neurons, indicating that the D620N VPS35 protein is fully functional. Our data raise the tantalizing possibility of a pathogenic interplay between mutant VPS35 and tau for inducing neurodegeneration in PD.


Assuntos
Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/fisiologia , Proteínas tau/metabolismo , Animais , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/fisiologia , Técnicas de Introdução de Genes , Masculino , Camundongos , Mutação , Doenças do Sistema Nervoso/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/fisiopatologia , Neuropatologia , Doença de Parkinson/genética , Transporte Proteico , alfa-Sinucleína/metabolismo , Proteínas tau/fisiologia
4.
Curr HIV/AIDS Rep ; 16(1): 66-75, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30778853

RESUMO

PURPOSE OF REVIEW: The purpose of this review is to summarize recent developments in PET imaging of neuropathologies underlying HIV-associated neurocognitive dysfunction (HAND). We concentrate on the recent post antiretroviral era (ART), highlighting clinical and preclinical brain PET imaging studies. RECENT FINDINGS: In the post ART era, PET imaging has been used to better understand perturbations of glucose metabolism, neuroinflammation, the function of neurotransmitter systems, and amyloid/tau protein deposition in the brains of HIV-infected patients and HIV animal models. Preclinical and translational findings from those studies shed a new light on the complex pathophysiology underlying HAND. The molecular imaging capabilities of PET in neuro-HIV are great complements for structural imaging modalities. Recent and future PET imaging studies can improve our understanding of neuro-HIV and provide biomarkers of disease progress that could be used as surrogate endpoints in the evaluation of the effectiveness of potential neuroprotective therapies.


Assuntos
Complexo AIDS Demência/diagnóstico por imagem , Complexo AIDS Demência/fisiopatologia , Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/fisiopatologia , Tomografia por Emissão de Pósitrons/métodos , Amiloide/fisiologia , Animais , Antirretrovirais/uso terapêutico , Biomarcadores , Glucose/metabolismo , Infecções por HIV/tratamento farmacológico , Humanos , Proteínas tau/fisiologia
5.
Amino Acids ; 51(3): 513-528, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30604097

RESUMO

Tauopathies consist of intracellular accumulation of hyperphosphorylated and aggregated microtubule protein tau, which remains a histopathological feature of Alzheimer's disease (AD) and frontotemporal dementia. L-Arginine is a semi-essential amino acid with a number of bioactive molecules. Its downstream metabolites putrescine, spermidine, and spermine (polyamines) are critically involved in microtubule assembly and stabilization. Recent evidence implicates altered arginine metabolism in the pathogenesis of AD. Using high-performance liquid chromatographic and mass spectrometric assays, the present study systematically determined the tissue concentrations of L-arginine and its nine downstream metabolites in the frontal cortex, hippocampus, parahippocampal region, striatum, thalamus, and cerebellum in male PS19 mice-bearing human tau P301S mutation at 4, 8, and 12-14 months of age. As compared to their wild-type littermates, PS19 mice displayed early and/or prolonged increases in L-ornithine and altered polyamine levels with age. There were also genotype- and age-related changes in L-arginine, L-citrulline, glutamine, glutamate, and γ-aminobutyric acid in a region- and/or chemical-specific manner. The results demonstrate altered brain arginine metabolism in PS19 mice with the most striking changes in L-ornithine, polyamines, and glutamate, indicating a shift of L-arginine metabolism to favor the arginase-polyamine pathway. Given the role of polyamines in maintaining microtubule stability, the functional significance of these changes remains to be explored in future research.


Assuntos
Arginina/metabolismo , Encéfalo/metabolismo , Modelos Animais de Doenças , Tauopatias/metabolismo , Proteínas tau/fisiologia , Animais , Encéfalo/patologia , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Tauopatias/patologia
6.
PLoS One ; 14(1): e0209573, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30608949

RESUMO

Glycosaminoglycans (GAGs), including heparan sulfates and chondroitin sulfates, are major components of the extracellular matrix. Upon interacting with heparin binding growth factors (HBGF), GAGs participate to the maintaintenance of tissue homeostasis and contribute to self-healing. Although several processes regulated by HBGF are altered in Alzheimer's disease, it is unknown whether the brain GAG capacities to bind and regulate the function of HBGF or of other heparin binding proteins, as tau, are modified in this disease. Here, we show that total sulfated GAGs from hippocampus of Alzheimer's disease have altered capacities to bind and potentiate the activities of growth factors including FGF-2, VEGF, and BDNF while their capacity to bind to tau is remarkable increased. Alterations of GAG structures and capacities to interact with and regulate the activity of heparin binding proteins might contribute to impaired tissue homeostasis in the Alzheimer's disease brain.


Assuntos
Doença de Alzheimer/metabolismo , Glicosaminoglicanos/metabolismo , Proteínas tau/fisiologia , Idoso , Idoso de 80 Anos ou mais , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Brasil , Sulfatos de Condroitina/metabolismo , Matriz Extracelular/metabolismo , Feminino , Fator 2 de Crescimento de Fibroblastos/metabolismo , Heparina/metabolismo , Heparitina Sulfato/metabolismo , Hipocampo/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Ligação Proteica , Lobo Temporal/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
7.
Med Sci (Paris) ; 34(11): 929-935, 2018 Nov.
Artigo em Francês | MEDLINE | ID: mdl-30526837

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disease primarily characterized by cognitive deficits and neuropathological lesions such as Tau aggregates and amyloid plaques, but also associated with metabolic and neuroendocrine abnormalities, such as impairment of cerebral insulin. However, the origin of these symptoms and their relationship to pathology and cognitive disorders remain poorly understood. Insulin is a hormone involved in the control of peripheral and central energy homeostasis, and insulin-resistant state has been linked to increased risk of dementia. It is now well established that brain insulin resistance can exacerbate Tau lesions. Conversely, recent data indicate that Tau protein can modulate insulin signalling in the brain, creating a vicious circle precipitating the pathological AD. This review aims to highlight our current understanding of the role of insulin in the brain and its relationship with Tau protein in the context of AD and Tauopathies.


Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Insulina/metabolismo , Tauopatias/metabolismo , Proteínas tau/fisiologia , Doença de Alzheimer/etiologia , Doença de Alzheimer/patologia , Animais , Encéfalo/patologia , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/metabolismo , Humanos , Resistência à Insulina/fisiologia , Transdução de Sinais/fisiologia , Tauopatias/etiologia , Tauopatias/patologia
8.
Mol Psychiatry ; 23(12): 2363-2374, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30171212

RESUMO

The typical abnormalities observed in the brain of Alzheimer's disease (AD) patients include synaptic alterations, neuronal death, brain inflammation, and the accumulation of protein aggregates in the form of amyloid plaques and neurofibrillary tangles. Despite the development of many animal and in vitro models for AD, there is a lack of an experimental approach that fully recapitulates essential aspects of the disease in human cells. Here, we report the generation of a new model to study AD, consisting of cerebral organoids (COs) produced from human-induced pluripotent stem cells (iPSCs). Under our experimental conditions, COs grow to form three-dimensional (3D) structures containing neural areas with cortical-like organization. Analysis of COs by histological and biochemical methods revealed that organoids produced from iPSCs derived from patients affected by familial AD or Down syndrome (DS) spontaneously develop over time pathological features of AD, including accumulation of structures highly reminiscent to amyloid plaques and neurofibrillary tangles. These pathological abnormalities were not observed in COs generated from various controls, including human iPSCs from healthy individuals, human iPSCs from patients affected by Creutzfeldt-Jakob disease, mouse embryonic stem cells (ESCs), or mouse iPSCs. These findings enable modeling genetic AD in a human cellular context in a 3D cortical-like tissue developed in vitro from patient-specific stem cells. This system provides a more relevant disease model compared to pre-existing methods and offers a new platform for discovery of novel targets and screening of drugs for therapeutic intervention.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Organoides/metabolismo , Proteínas tau/metabolismo , Idoso , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/fisiologia , Encéfalo/metabolismo , Técnicas de Cultura de Células/métodos , Córtex Cerebral , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Lactente , Masculino , Pessoa de Meia-Idade , Emaranhados Neurofibrilares/patologia , Neurônios/metabolismo , Fosforilação , Placa Amiloide/metabolismo , Proteínas tau/genética , Proteínas tau/fisiologia
9.
Brain ; 141(9): 2685-2699, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30084913

RESUMO

Traumatic brain injury is a risk factor for subsequent neurodegenerative disease, including chronic traumatic encephalopathy, a tauopathy mostly associated with repetitive concussion and blast, but not well recognized as a consequence of severe traumatic brain injury. Here we show that a single severe brain trauma is associated with the emergence of widespread hyperphosphorylated tau pathology in a proportion of humans surviving late after injury. In parallel experimental studies, in a model of severe traumatic brain injury in wild-type mice, we found progressive and widespread tau pathology, replicating the findings in humans. Brain homogenates from these mice, when inoculated into the hippocampus and overlying cerebral cortex of naïve mice, induced widespread tau pathology, synaptic loss, and persistent memory deficits. These data provide evidence that experimental brain trauma induces a self-propagating tau pathology, which can be transmitted between mice, and call for future studies aimed at investigating the potential transmissibility of trauma associated tau pathology in humans.


Assuntos
Lesões Encefálicas Traumáticas/complicações , Tauopatias/etiologia , Tauopatias/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Animais , Encéfalo/patologia , Concussão Encefálica/patologia , Lesões Encefálicas Traumáticas/fisiopatologia , Córtex Cerebral/patologia , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Doenças Neurodegenerativas/patologia , Fosforilação , Proteínas tau/metabolismo , Proteínas tau/fisiologia
10.
Brain ; 141(9): 2740-2754, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30052812

RESUMO

Alzheimer's disease is characterized by the histopathological presence of amyloid-ß plaques and tau-containing neurofibrillary tangles. Microglial activation is also a recognized pathological component. The relationship between microglial activation and protein aggregation is still debated. We investigated the relationship between amyloid plaques, tau tangles and activated microglia using PET imaging. Fifty-one subjects (19 healthy controls, 16 mild cognitive impairment and 16 Alzheimer's disease subjects) participated in the study. All subjects had neuropsychometric testing, MRI, amyloid (18F-flutemetamol), and microglial (11C-PBR28) PET. All subjects with mild cognitive impairment and Alzheimer's disease and eight of the controls had tau (18F-AV1451) PET. 11C-PBR28 PET was analysed using Logan graphical analysis with an arterial plasma input function, while 18F-flutemetamol and 18F-AV1451 PET were analysed as target:cerebellar ratios to create parametric standardized uptake value ratio maps. Biological parametric mapping in the Statistical Parametric Mapping platform was used to examine correlations between uptake of tracers at a voxel-level. There were significant widespread clusters of positive correlation between levels of microglial activation and tau aggregation in both the mild cognitive impairment (amyloid-positive and amyloid-negative) and Alzheimer's disease subjects. The correlations were stronger in Alzheimer's disease than in mild cognitive impairment, suggesting that these pathologies increase together as disease progresses. Levels of microglial activation and amyloid deposition were also correlated, although in a different spatial distribution; correlations were stronger in mild cognitive impairment than Alzheimer's subjects, in line with a plateauing of amyloid load with disease progression. Clusters of positive correlations between microglial activation and protein aggregation often targeted similar areas of association cortex, indicating that all three processes are present in specific vulnerable brain areas. For the first time using PET imaging, we show that microglial activation can correlate with both tau aggregation and amyloid deposition. This confirms the complex relationship between these processes. These results suggest that preventative treatment for Alzheimer's disease should target all three processes.


Assuntos
Doença de Alzheimer/patologia , Disfunção Cognitiva/patologia , Microglia/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/fisiologia , Amiloidose/patologia , Encéfalo/patologia , Mapeamento Encefálico/métodos , Disfunção Cognitiva/metabolismo , Progressão da Doença , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Microglia/fisiologia , Pessoa de Meia-Idade , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/fisiologia , Testes Neuropsicológicos , Placa Amiloide/patologia , Tomografia por Emissão de Pósitrons/métodos , Proteínas tau/metabolismo , Proteínas tau/fisiologia
11.
Expert Rev Neurother ; 18(7): 603-616, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29902389

RESUMO

INTRODUCTION: Progressive supranuclear palsy (PSP) is associated with microtubule-associated protein tau dysfunction. Originally thought to result in a syndrome of atypical Parkinsonism, vertical supranuclear gaze palsy, and cognitive impairment, several additional phenotypic manifestations of PSP pathology have been described over the last 20 years. Furthermore, prototypical PSP features may develop late, making early diagnosis challenging. Areas covered: An in-depth view of emerging knowledge in the field of PSP. Advances in clinicopathologic correlation, blood, cerebrospinal, and more importantly neuroimaging biomarkers are discussed in light of the 2017 PSP diagnostic criteria by the Movement Disorders Society Study Group. Discoveries related to molecular pathogenesis have enabled development of disease-modifying therapies for PSP, many of which are currently under investigation. Expert commentary: Despite remarkable growth in our knowledge of tauopathies like PSP, early and accurate clinical prediction of PSP neuropathology remains challenging. Clinical phenotypes overlap, and biomarkers are nonspecific. There is a pressing need for disease-specific biomarkers that enable timely identification of patients and biomarker-driven investigation of disease-modifying therapies.


Assuntos
Paralisia Supranuclear Progressiva/diagnóstico , Biomarcadores , Humanos , Neuroimagem , Fenótipo , Paralisia Supranuclear Progressiva/epidemiologia , Paralisia Supranuclear Progressiva/fisiopatologia , Paralisia Supranuclear Progressiva/terapia , Proteínas tau/fisiologia
12.
Gene ; 664: 1-11, 2018 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-29684490

RESUMO

Tau is a multifunctional protein, originally identified as a cytoplasmic protein associated with microtubules. It is codified by the MAPT gene, and the alternative splicing, in the neuronal cells, results in six different isoforms. Tau was subsequently observed in the cell nucleus, where its function is not yet clearly understood. Here, we studied the MAPT gene and the cellular localization of the AT8 and Tau-1 epitopes of Tau protein, in the SK-N-BE cell line, which differentiates in neuronal-like cells after retinoic acid treatment. These epitopes correspond to the phosphorylated Ser202/Thr205 and unphosphorylated Pro189/Gly207 amino acid residues, respectively, possibly involved in conformational changes of the protein. Our results demonstrated the presence of the smaller Tau isoform (352 amino acids), whose amount increases in differentiated SK-N-BE cells, with Tau-1/AT8 nuclear distribution related to the differentiation process. Tau-1 showed a spot-like nucleolar localization, in both replicative and differentiated cells, while AT8 was only detected in the differentiated cells, diffusely occupying the entire nucleolar region. Moreover, in the replicative cells exposed to actinomycin-D, AT8 and Tau-1 move to the nucleolar periphery and colocalize, in few spots, with the upstream binding transcription factor (UBTF). Our results, also obtained with lymphocytes exposed to the mitogenic compound phytohaemagglutinin, indicate the AT8 epitope of Tau as a marker of neuronal cell differentiation, whose presence in the nucleolus appears to be related to rDNA transcriptional inactivation.


Assuntos
Diferenciação Celular/fisiologia , Nucléolo Celular/metabolismo , Neurônios/fisiologia , Proteínas tau/fisiologia , Processamento Alternativo , Biomarcadores/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Nucléolo Celular/efeitos dos fármacos , DNA Ribossômico/metabolismo , Dactinomicina/farmacologia , Epitopos/metabolismo , Imunofluorescência , Humanos , Linfócitos , Mitose/efeitos dos fármacos , Fosforilação , Fito-Hemaglutininas/farmacologia , Proteínas Pol1 do Complexo de Iniciação de Transcrição/metabolismo , Isoformas de Proteínas/fisiologia , Serina/metabolismo , Treonina/metabolismo , Tretinoína/farmacologia
13.
J Biol Chem ; 293(22): 8462-8472, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29632073

RESUMO

Tau hyperphosphorylation at several sites, including those close to the microtubule domain region (MDr), is considered a key pathological event in the development of Alzheimer's disease (AD). Recent studies indicate that at the very early stage of this disease, increased phosphorylation in Tau's MDr domain correlates with reduced levels of neuronal excitability. Mechanistically, we show that pyramidal neurons and some parvalbumin-positive interneurons in 1-month-old triple-transgenic AD mice accumulate hyperphosphorylated Tau protein and that this accumulation correlates with changes in theta oscillations in hippocampal neurons. Pyramidal neurons from young triple-transgenic AD mice exhibited less spike accommodation and power increase in subthreshold membrane oscillations. Furthermore, triple-transgenic AD mice challenged with the potassium channel blocker 4-aminopyridine had reduced theta amplitude compared with 4-aminopyridine-treated control mice and, unlike these controls, displayed no seizure-like activity after this challenge. Collectively, our results provide new insights into AD pathogenesis and suggest that increases in Tau phosphorylation at the initial stages of the disease represent neuronal responses that compensate for brain circuit overexcitation.


Assuntos
Potenciais de Ação , Doença de Alzheimer/patologia , Modelos Animais de Doenças , Hipocampo/patologia , Células Piramidais/patologia , Ritmo Teta/fisiologia , Proteínas tau/fisiologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Animais , Células Cultivadas , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Fosforilação , Células Piramidais/metabolismo
14.
Biomed J ; 41(1): 21-33, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29673549

RESUMO

Alzheimer's Disease (AD) is a chronic neurodegenerative disorder and the most common type of dementia (60-80% of cases). In 2016, nearly 44 million people were affected by AD or related dementia. AD is characterized by progressive neuronal damages leading to subtle and latter obvious decline in cognitive functions including symptoms such as memory loss or confusion, which ultimately require full-time medical care. Its neuropathology is defined by the extracellular accumulation of amyloid-ß (Aß) peptide into amyloid plaques, and intraneuronal neurofibrillary tangles (NFT) consisting of aggregated hyper- and abnormal phosphorylation of tau protein. The latter, identified also as Tau pathology, is observed in a broad spectrum of neurological diseases commonly referred to as "Tauopathies". Besides these lesions, sustained neuroinflammatory processes occur, involving notably micro- and astro-glial activation, which contribute to disease progression. Recent findings from genome wide association studies further support an instrumental role of neuroinflammation. While the interconnections existing between this innate immune response and the amyloid pathogenesis are widely characterized and described as complex, elaborated and evolving, only few studies focused on Tau pathology. An adaptive immune response takes place conjointly during the disease course, as indicated by the presence of vascular and parenchymal T-cell in AD patients' brain. The underlying mechanisms of this infiltration and its consequences with regards to Tau pathology remain understudied so far. In the present review, we highlight the interplays existing between Tau pathology and the innate/adaptive immune responses.


Assuntos
Doença de Alzheimer/etiologia , Inflamação/etiologia , Tauopatias/etiologia , Proteínas tau/fisiologia , Imunidade Adaptativa , Barreira Hematoencefálica , Humanos , Imunidade Inata , Neuroglia/fisiologia , Fosforilação
15.
Sci Rep ; 8(1): 3184, 2018 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-29453339

RESUMO

Tau plays a pivotal role in the pathogenesis of neurodegenerative disorders: mutations in the gene encoding for tau (MAPT) are linked to Fronto-temporal Dementia (FTD) and hyper-phosphorylated aggregates of tau forming neurofibrillary tangles (NFTs) that constitute a pathological hallmark of Alzheimer disease (AD) and FTD. Accordingly, tau is a favored therapeutic target for the treatment of these diseases. Given the criticality of tau to dementia's pathogenesis and therapy, it is important to understand the physiological function of tau in the central nervous system. Analysis of Mapt knock out (Mapt-/-) mice has yielded inconsistent results. Some studies have shown that tau deletion does not alter memory while others have described synaptic plasticity and memory alterations in Mapt-/- mice. To help clarifying these contrasting results, we analyzed a distinct Mapt-/- model on a B6129PF3/J genetic background. We found that tau deletion leads to aging-dependent short-term memory deficits, hyperactivity and synaptic plasticity defects. In contrast, Mapt+/- mice only showed a mild short memory deficit in the novel object recognition task. Thus, while tau is important for normal neuronal functions underlying learning and memory, partial reduction of tau expression may have fractional deleterious effects.


Assuntos
Aprendizagem/fisiologia , Plasticidade Neuronal/fisiologia , Proteínas tau/fisiologia , Doença de Alzheimer/metabolismo , Animais , Encéfalo/patologia , Hipocampo/patologia , Masculino , Memória/fisiologia , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Emaranhados Neurofibrilares/metabolismo , Neurônios/metabolismo , Fosforilação , Proteínas tau/genética , Proteínas tau/metabolismo
16.
Mol Psychiatry ; 23(6): 1530-1540, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-28696431

RESUMO

Changes in synaptic excitability and reduced brain metabolism are among the earliest detectable alterations associated with the development of Alzheimer's disease (AD). Stimulation of synaptic activity has been shown to be protective in models of AD beta-amyloidosis. Remarkably, deep brain stimulation (DBS) provides beneficial effects in AD patients, and represents an important therapeutic approach against AD and other forms of dementia. While several studies have explored the effect of synaptic activation on beta-amyloid, little is known about Tau protein. In this study, we investigated the effect of synaptic stimulation on Tau pathology and synapses in in vivo and in vitro models of AD and frontotemporal dementia (FTD). We found that chronic DBS or chemically induced synaptic stimulation reduced accumulation of pathological forms of Tau and protected synapses, while chronic inhibition of synaptic activity worsened Tau pathology and caused detrimental effects on pre- and post-synaptic markers, suggesting that synapses are affected. Interestingly, degradation via the proteasomal system was not involved in the reduction of pathological Tau during stimulation. In contrast, chronic synaptic activation promoted clearance of Tau oligomers by autophagosomes and lysosomes. Chronic inhibition of synaptic activity resulted in opposite outcomes, with build-up of Tau oligomers in enlarged auto-lysosomes. Our data indicate that synaptic activity counteracts the negative effects of Tau in AD and FTD by acting on autophagy, providing a rationale for therapeutic use of DBS and synaptic stimulation in tauopathies.


Assuntos
Doença de Alzheimer/metabolismo , Sinapses/metabolismo , Tauopatias/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Autofagia/fisiologia , Encéfalo/metabolismo , Estimulação Encefálica Profunda/métodos , Modelos Animais de Doenças , Feminino , Demência Frontotemporal/metabolismo , Hipocampo/patologia , Humanos , Lisossomos/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Fármacos Neuroprotetores/metabolismo , Proteínas tau/fisiologia
17.
Rev. neurol. (Ed. impr.) ; 65(10): 457-468, 16 nov., 2017. tab, graf, ilus
Artigo em Espanhol | IBECS | ID: ibc-169069

RESUMO

Introducción. Numerosos trastornos neurodegenerativos se han asociado directamente a la acumulación de fibras amiloides. Estas fibras están formadas por proteínas o péptidos con conformaciones alteradas y que se agregan in vivo en asociación con polisacáridos de tipo heparán sulfatos. Objetivos. Examinar los conceptos más recientes sobre la biología de los heparán sulfatos y su papel en la agregación del péptido Abeta, de la proteína tau, de la alfa-sinucleína y de los priones, y analizar sus implicaciones en trastornos neurodegenerativos como las enfermedades de Alzheimer y de Parkinson y las enfermedades priónicas. Desarrollo. In vitro, los heparán sulfatos han desempeñado un papel importante en el proceso de oligomerización y fibrilación de proteínas o péptidos amiloidógenos, en la estabilización de estos cuerpos y su resistencia a la proteólisis, participando así en la formación de una gran variedad de fibras amiloides. Los heparán sulfatos se han relacionado también con el proceso de internalización de fibras proamiloides durante el proceso de propagación intercelular (spreading) considerado como central en la evolución de las proteinopatías, cuyo mejor ejemplo es la enfermedad de Alzheimer. Conclusión. Este trabajo sugiere que las estructuras finas de los heparán sulfatos, sus localizaciones celulares y tisulares, así como sus concentraciones locales, pueden regular los procesos de amiloidosis. Avances en la comprensión de esta área de la gliconeurobiología permitirán mejorar la comprensión de los mecanismos celulares y moleculares del proceso neurodegenerativo (AU)


Introduction. A number of neurodegenerative disorders have been linked directly to the accumulation of amyloid fibres. These fibres are made up of proteins or peptides with altered structures and which join together in vivo in association with heparan sulphate-type polysaccharides. AIMS. To examine the most recent concepts in the biology of heparan sulphates and their role in the aggregation of the peptide Abeta, of tau protein, of alpha-synuclein and of prions. The study also seeks to analyse their implications in neurodegenerative disorders such as Alzheimers and Parkinson’s disease and prion diseases. Development. In vitro, heparan sulphates have played an important role in the process of oligomerisation and fibrillation of amyloidogenic proteins or peptides, in the stabilisation of these bodies and their resistance to proteolysis, thereby participating in the formation of a wide range of amyloid fibres. Heparan sulphates have also been related to the internalisation of pro-amyloid fibres during the process of intercellular propagation (spreading), which is considered to be crucial in the development of proteinopathies, the best example of which is Alzheimers disease. Conclusion This study suggests that the fine structures of heparan sulphates, their localisation in cells and tissues, together with their local concentration, may regulate the amyloidosis processes. The advances made in the understanding of this area of glyconeurobiology will make it possible to improve the understanding of the cell and molecular mechanisms underlying the neurodegenerative process (AU)


Assuntos
Humanos , Heparitina Sulfato/farmacocinética , Amiloidose/fisiopatologia , Doença de Parkinson/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Doenças Priônicas/fisiopatologia , Doença de Alzheimer/fisiopatologia , Agregação Patológica de Proteínas/fisiopatologia , Glicosaminoglicanos/farmacocinética , Proteínas tau/fisiologia , alfa-Sinucleína/fisiologia
18.
Curr Opin Neurol ; 30(6): 589-598, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28914736

RESUMO

PURPOSE OF REVIEW: The purpose of this review is to provide an update on the role of tau beyond the stabilization of microtubules and on the clinical, pathological, diagnostic and therapeutic aspects of tauopathies. RECENT FINDINGS: Beyond its function as a microtubule-associated tau protein, tau is also involved in gene regulation, signal transduction and metabolism. Experimental models allow for the development of new diagnostic and therapeutic tools. Tauopathies encompass different disorders that may manifest with various clinical syndromes. Differential diagnosis with other proteinopathies is still challenging. Cerebrospinal fluid biomarkers and radiotracers were extensively studied in the last year. Although diagnostic accuracy remains deceiving in non-Alzheimer's disease tauopathies, positron emission tomography tau tracers could be used to monitor disease progression. SUMMARY: Despite the advent of novel therapeutic approaches and the increasing number of clinical trials in tauopathies, accurate clinical diagnosis is still an unmet need and better tau biomarkers are still desperately needed. Although primary taupathies are rare and heterogeneous disorders, their combined prevalence and the importance of tau disorder in Alzheimer's disease and secondary tauopathies makes research on tauopathy a priority - because it could benefit many patients.


Assuntos
Demência/diagnóstico , Tauopatias/diagnóstico , Proteínas tau/fisiologia , Animais , Demência/tratamento farmacológico , Humanos , Tauopatias/tratamento farmacológico
19.
Nat Commun ; 8(1): 693, 2017 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-28947735

RESUMO

Cells from Bloom's syndrome patients display genome instability due to a defective BLM and the downregulation of cytidine deaminase. Here, we use a genome-wide RNAi-synthetic lethal screen and transcriptomic profiling to identify genes enabling BLM-deficient and/or cytidine deaminase-deficient cells to tolerate constitutive DNA damage and replication stress. We found a synthetic lethal interaction between cytidine deaminase and microtubule-associated protein Tau deficiencies. Tau is overexpressed in cytidine deaminase-deficient cells, and its depletion worsens genome instability, compromising cell survival. Tau is recruited, along with upstream-binding factor, to ribosomal DNA loci. Tau downregulation decreases upstream binding factor recruitment, ribosomal RNA synthesis, ribonucleotide levels, and affects ribosomal DNA stability, leading to the formation of a new subclass of human ribosomal ultrafine anaphase bridges. We describe here Tau functions in maintaining survival of cytidine deaminase-deficient cells, and ribosomal DNA transcription and stability. Moreover, our findings for cancer tissues presenting concomitant cytidine deaminase underexpression and Tau upregulation open up new possibilities for anti-cancer treatment.Cytidine deaminase (CDA) deficiency leads to genome instability. Here the authors find a synthetic lethal interaction between CDA and the microtubule-associated protein Tau deficiencies, and report that Tau depletion affects rRNA synthesis, ribonucleotide pool balance, and rDNA stability.


Assuntos
Síndrome de Bloom/genética , DNA Ribossômico/metabolismo , Proteínas tau/fisiologia , Síndrome de Bloom/patologia , Sobrevivência Celular , Citidina Desaminase/deficiência , Regulação para Baixo , Instabilidade Genômica , Células HeLa , Humanos , RecQ Helicases/genética , Regulação para Cima , Proteínas tau/genética , Proteínas tau/metabolismo
20.
Sci Rep ; 7(1): 6238, 2017 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-28740171

RESUMO

Alzheimer's disease (AD) is a degenerative disorder typified by progressive deterioration of memory and the appearance of ß-amyloid peptide (Aß)-rich senile plaques. Recently we have identified a novel function of a patented formulation of modified Huanglian-Jie-Tu-Tang (HLJDT-M), a Chinese herbal medicine, in treating AD in in vitro studies (US patent No. 9,375,457). HLJDT-M is a formulation composed of Rhizoma Coptitis, Cortex Phellodendri and Fructus Gardeniae without Radix Scutellariae. Here, we assessed the efficacy of HLJDT-M on a triple transgenic mouse model of AD (3XTg-AD). Oral administration of HLJDT-M ameliorated the cognitive dysfunction of 3XTg-AD mice and lessened the plaque burden. In addition, biochemical assays revealed a significant decrease in levels of detergent-soluble and acid-soluble Aß via decreasing the levels of full length amyloid-ß precursor protein (FL-APP) and C-terminal fragments of APP (CTFs) in brain lysates of HLJDT-M-treated mice. HLJDT-M treatment also significantly reduced the levels of FL-APP and CTFs in N2a/SweAPP cells. In contrast, treatment using the classical formula HLJDT did not reduce the memory impairment of 3XTg-AD mice and, rather, increased the Aß/Fl-APP/CTFs in both animal and cell culture studies. Altogether, our study indicates that HLJDT-M is a promising herbal formulation to prevent and/or cure AD.


Assuntos
Doença de Alzheimer/complicações , Precursor de Proteína beta-Amiloide/fisiologia , Medicamentos de Ervas Chinesas/química , Transtornos da Memória/tratamento farmacológico , Extratos Vegetais/farmacocinética , Placa Amiloide/prevenção & controle , Presenilina-1/fisiologia , Proteínas tau/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Camundongos , Camundongos Transgênicos , Placa Amiloide/etiologia , Placa Amiloide/patologia
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