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1.
Neuropathol Appl Neurobiol ; 49(4): e12931, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37565253

RESUMEN

BACKGROUND: Reduced folate status and elevated levels of circulating homocysteine are modifiable risk factors for cognitive decline and dementia. Disturbances in one-carbon metabolism are associated with the pathological accumulation of phosphorylated tau, a hallmark feature of prevalent dementia, including Alzheimer's disease and subgroups of frontotemporal dementia. METHODS: Here, using transgenic TAU58/2 mouse models of human tauopathy, we tested whether dietary supplementation with L-methylfolate (the active folate form), choline and betaine can reduce tau phosphorylation and associated behavioural phenotypes. RESULTS: TAU58/2 mice fed with the methyl donor-enriched diet showed reduced phosphorylation of tau at the pathological S202 (CP13) and S396/S404 (PHF-1) epitopes and alleviation of associated motor and learning deficits. Compared with mice on the control diet, the decrease in cortical phosphorylated tau levels in mice fed with the methyl donor-enriched diet was associated with enhanced methylation of protein phosphatase 2A, the major brain tau Ser/Thr phosphatase. It also correlated with a reduction in protein levels of Fyn, a tau tyrosine kinase that plays a central role in mediating pathological tau-induced neurodegeneration. Conversely, Fyn expression levels were increased in mice with deficiencies in folate metabolism. CONCLUSIONS: Our findings provide the first experimental evidence that boosting one-carbon metabolism with L-methylfolate, choline and betaine can mitigate key pathological, learning and motor deficits in a tauopathy mouse model. They give support to using a combination of methyl donors as a preventive or disease-modifying strategy for tauopathies.


Asunto(s)
Enfermedad de Alzheimer , Tauopatías , Ratones , Humanos , Animales , Proteína Fosfatasa 2/metabolismo , Proteínas tau/metabolismo , Betaína , Tauopatías/patología , Ratones Transgénicos , Enfermedad de Alzheimer/metabolismo , Fosforilación , Modelos Animales de Enfermedad , Ácido Fólico , Colina , Suplementos Dietéticos , Carbono
2.
Biosensors (Basel) ; 12(10)2022 Oct 17.
Artículo en Inglés | MEDLINE | ID: mdl-36291020

RESUMEN

Alzheimer's disease (AD) is the most common form of dementia. The most convincing biomarkers in the blood for AD are currently ß-amyloid (Aß) and Tau protein because amyloid plaques and neurofibrillary tangles are pathological hallmarks in the brains of patients with AD. The development of assay technologies in diagnosing early-stage AD is very important. The study of human AD subjects is hindered by ethical and technical limitations. Thus, many studies have therefore turned to AD animal models, such as Drosophila melanogaster, to explore AD pathology. However, AD biomarkers such as Aß and p-Tau protein in Drosophilamelanogaster occur at extremely low levels and are difficult to detect precisely. In this study, we applied the immunomagnetic reduction (IMR) technology of nanoparticles for the detection of p-Tau expressions in hTauR406W flies, an AD Drosophila model. Furthermore, we used IMR technology as a biosensor in the therapeutic evaluation of Chinese herbal medicines in hTauR406W flies with Tau-induced toxicity. To uncover the pathogenic pathway and identify therapeutic interventions of Chinese herbal medicines in Tau-induced toxicity, we modeled tauopathy in the notum of hTauR406W flies. Our IMR data showed that the selected Chinese herbal medicines can significantly reduce p-Tau expressions in hTauR406W flies. Using evidence of notal bristle quantification and Western blotting analysis, we confirmed the validity of the IMR data. Thus, we suggest that IMR can serve as a new tool for measuring tauopathy and therapeutic evaluation of Chinese herbal medicine in an AD Drosophila model.


Asunto(s)
Enfermedad de Alzheimer , Técnicas Biosensibles , Medicamentos Herbarios Chinos , Tauopatías , Animales , Humanos , Proteínas tau , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Drosophila/metabolismo , Medicamentos Herbarios Chinos/uso terapéutico , Drosophila melanogaster/metabolismo , Tauopatías/tratamiento farmacológico , Péptidos beta-Amiloides , Tecnología
3.
Front Pharmacol ; 13: 903119, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35662729

RESUMEN

Global forecasts for prevalence of Alzheimer's Disease (AD) estimate that 152.8 million people will have dementia in 2050, a sharp rise from 57.4 million in 2019 (GBD 2019). This rise can be attributable to increases in population growth and aging, but in the absence of disease-modifying therapies it poses a huge societal challenge that must be addressed urgently. One way to combat this challenge is to explore the utility of holistic treatments that may protect against AD, including traditional herbs, spices and other nutraceuticals that are pharmacologically safe, inexpensive and readily available. In this light, the spice turmeric, and its active ingredient curcumin, has been investigated as a potential holistic treatment for AD over the past 2 decades; however, promising results with animal studies have not translated to success in clinical trials. One issue is that most animal models examining the effects of curcumin and curcumin derivatives in AD have been done with a focus at ameliorating amyloid pathology. Due to the limited success of Amyloid-ß-based drugs in recent clinical trials, tau-focused therapeutics provide a promising alternative. In this article, we aim to provide a clearer picture of what is currently known about the effectiveness of curcumin and curcumin derivatives to ameliorate tau pathology. Tau focused studies may help inform more successful clinical studies by placing greater emphasis on the development and optimised delivery of curcumin derivatives that more effectively target tau pathology.

4.
Biomedicines ; 10(4)2022 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-35453617

RESUMEN

The tau protein aggregation inhibitor hydromethylthionine mesylate (HMTM) was shown recently to have concentration-dependent pharmacological activity in delaying cognitive decline and brain atrophy in phase 3 Alzheimer's disease (AD) clinical trials; the activity was reduced in patients receiving symptomatic therapies. The methylthionine (MT) moiety has been reported to increase the clearance of pathological tau and to enhance mitochondrial activity, which is impaired in AD patients. In line 1 (L1) mice (a model of AD), HMTM (5/15 mg/kg) was administered either as a monotherapy or as an add-on to a chronic administration with the cholinesterase inhibitor rivastigmine (0.1/0.5 mg/kg) to explore mitochondrial function and energy substrate utilization as potential targets of drug interference. Compared with wild-type NMRI mice, the L1 mice accumulated greater levels of l-lactate and of the LDH-A subunit responsible for the conversion of pyruvate into l-lactate. In contrast, the levels of LDH-B and mitochondrial ETC subunits and the activity of complexes I and IV was not altered in the L1 mice. The activity of complex I and complex IV tended to increase with the HMTM dosing, in turn decreasing l-lactate accumulation in the brains of the L1 mice, despite increasing the levels of LDH-A. The chronic pre-dosing of the L1 mice with rivastigmine partially prevented the enhancement of the activity of complexes I and IV by HMTM and the increase in the levels of LDH-A while further reducing the levels of l-lactate. Thus, HMTM in combination with rivastigmine leads to a depletion in the energy substrate l-lactate, despite bioenergetic production not being favoured. In this study, the changes in l-lactate appear to be regulated by LDH-A, since neither of the experimental conditions affected the levels of LDH-B. The data show that HMTM monotherapy facilitates the use of substrates for energy production, particularly l-lactate, which is provided by astrocytes, additionally demonstrating that a chronic pre-treatment with rivastigmine prevented most of the HMTM-associated effects.

5.
Biosci Rep ; 41(8)2021 08 27.
Artículo en Inglés | MEDLINE | ID: mdl-34308969

RESUMEN

Misfolded, pathological tau protein propagates from cell to cell causing neuronal degeneration in Alzheimer's disease and other tauopathies. The molecular mechanisms of this process have remained elusive. Unconventional secretion of tau takes place via several different routes, including direct penetration through the plasma membrane. Here, we show that tau secretion requires membrane interaction via disulphide bridge formation. Mutating residues that reduce tau interaction with membranes or formation of disulphide bridges decrease both tau secretion from cells, and penetration through artificial lipid membranes. Our results demonstrate that tau is indeed able to penetrate protein-free membranes in a process independent of active cellular processes and that both membrane interaction and disulphide bridge formation are needed for this process. QUARK-based de novo modelling of the second and third microtubule-binding repeat domains (MTBDs), in which the two cysteine residues of 4R isoforms of tau are located, supports the concept that this region of tau could form transient amphipathic helices for membrane interaction.


Asunto(s)
Membrana Celular/metabolismo , Disulfuros/metabolismo , Neuronas/metabolismo , Proteínas tau/metabolismo , Animales , Línea Celular Tumoral , Cisteína , Disulfuros/química , Humanos , Ratones , Modelos Moleculares , Mutación , Conformación Proteica en Hélice alfa , Pliegue de Proteína , Dominios y Motivos de Interacción de Proteínas , Vías Secretoras , Relación Estructura-Actividad , Proteínas tau/química , Proteínas tau/genética
6.
Cell Adh Migr ; 15(1): 84-100, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-33724164

RESUMEN

Microglia, the resident immune cells, were found to be activated to inflammatory phenotype in Alzheimer's disease (AD). The extracellular burden of amyloid-ß plaques and Tau seed fabricate the activation of microglia. The seeding effect of extracellular Tau species is an emerging aspect to study about Tauopathies in AD. Tau seeds enhance the propagation of disease along with its contribution to microglia-mediated inflammation. The excessive neuroinflammation cumulatively hampers phagocytic function of microglia reducing the clearance of extracellular protein aggregates. Omega-3 fatty acids, especially docosahexaenoic acid and eicosapentaenoic acid, are recognized to induce anti-inflammatory phenotype of microglia. In addition to increased cytokine production, omega-3 fatty acids enhance phagocytic receptors expression in microglia. In this study, we have observed the phagocytosis of extracellular Tau in the presence of α-linolenic acid (ALA). The increased phagocytosis of extracellular Tau monomer and aggregates have been observed upon ALA exposure to microglia cells. After internalization, the degradation status of Tau has been studied with early and late endosomal markers Rab5 and Rab7. Further, the lysosome-mediated degradation of internalized Tau was studied with LAMP-2A, a lysosome marker. The enhanced migratory ability in the presence of ALA could be beneficial for microglia to access the target and clear it. The increased migration of microglia was found to induce the microtubule-organizing center repolarization. The data indicate that the dietary fatty acids ALA could significantly enhance phagocytosis and intracellular degradation of internalized Tau. Our results suggest that microglia could be influenced to reduce extracellular Tau seed with dietary fatty acids.


Asunto(s)
Enfermedad de Alzheimer , Microglía , Humanos , Enfermedades Neuroinflamatorias , Fagocitosis , Ácido alfa-Linolénico , Proteínas tau
7.
Eur J Med Chem ; 209: 112915, 2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-33139110

RESUMEN

Alzheimer's disease (AD) is the most common form of dementia characterized by presence of extracellular amyloid plaques and intracellular neurofibrillary tangles composed of tau protein. Currently there are close to 50 million people living with dementia and this figure is expected to increase to 75 million by 2030 putting a huge burden on the economy due to the health care cost. Considering the effects on quality of life of patients and the increasing burden on the economy, there is an enormous need of new disease modifying therapies to tackle this disease. The current therapies are dominated by only symptomatic treatments including cholinesterase inhibitors and N-methyl-D-aspartate receptor blockers but no disease modifying treatments exist so far. After several failed attempts to develop drugs against amyloidopathy, tau targeting approaches have been in the main focus of drug development against AD. After an overview of the tauopathy in AD, this review summarizes recent findings on the development of small molecules as therapeutics targeting tau modification, aggregation, and degradation, and tau-oriented multi-target directed ligands. Overall, this work aims to provide a comprehensive and critical overview of small molecules which are being explored as a lead candidate for discovering drugs against tauopathy in AD.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Fármacos Neuroprotectores/química , Proteínas tau/metabolismo , Animales , Benzodioxoles/farmacología , Inhibidores de la Colinesterasa/farmacología , Colinesterasas/metabolismo , Curcumina/farmacología , Humanos , Terapia Molecular Dirigida , Ovillos Neurofibrilares/metabolismo , Fármacos Neuroprotectores/farmacología , Fosforilación , Placa Amiloide/metabolismo , Agregación Patológica de Proteínas/prevención & control , Procesamiento Proteico-Postraduccional , Quinazolinas/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Tiadiazoles/farmacología
8.
J Alzheimers Dis ; 77(4): 1705-1715, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32925070

RESUMEN

BACKGROUND: Alterations in the methionine cycle and abnormal tau phosphorylation are implicated in many neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia. rTg4510 mice express mutant human P301L tau and are a model of tau hyperphosphorylation. The cognitive deficit seen in these animals correlates with a burden of hyperphosphorylated tau and is a model to test therapies aimed at lowering phosphorylated tau. OBJECTIVE: This study aimed to increase protein phosphatase 2A activity through supplementation of S-adenosylmethionine and analyze the effect on spatial memory and tau in treated animals. METHODS: 6-month-old rTg4510 mice were treated with 100 mg/kg S-adenosylmethionine by oral gavage for 3 weeks. Spatial recognition memory was tested in the Y-maze. Alterations to phosphorylated tau and protein phosphatase 2A were explored using immunohistochemistry, western blot, and enzyme-linked immunosorbent assays. RESULTS: Treatment with S-adenosylmethionine increased the Y-maze novel arm exploration time and increased both the expression and activity of protein phosphatase 2A. Furthermore, treatment reduced the number of AT8 positive neurons and reduced the expression of phosphorylated tau (Ser202/Thr205). S-adenosylmethionine contributes to multiple pathways in neuronal homeostasis and neurodegeneration. CONCLUSION: This study shows that supplementation with S-adenosylmethionine stabilizes the heterotrimeric form of PP2A resulting in an increase the enzymatic activity, a reduced level of pathological tau, and improved cognition.


Asunto(s)
Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Proteína Fosfatasa 2/metabolismo , S-Adenosilmetionina/administración & dosificación , Proteínas tau/antagonistas & inhibidores , Proteínas tau/metabolismo , Administración Oral , Animales , Disfunción Cognitiva/genética , Ratones , Ratones de la Cepa 129 , Ratones Transgénicos , Fosforilación/efectos de los fármacos , Fosforilación/fisiología , Estabilidad Proteica/efectos de los fármacos
9.
J Neuroinflammation ; 17(1): 93, 2020 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-32209097

RESUMEN

Microglial polarization is an utmost important phenomenon in Alzheimer's disease that influences the brain environment. Polarization depends upon the types of responses that cells undergo, and it is characterized by receptors present on the cell surface and the secreted cytokines to the most. The expression of receptors on the surface is majorly influenced by internal and external factors such as dietary lipids. Types of fatty acids consumed through diet influence the brain environment and glial cell phenotype and types of receptors on microglia. Reports suggest that dietary habits influence microglial polarization and the switching of microglial phenotype is very important in neurodegenerative diseases. Omega-3 fatty acids have more influence on the brain, and they are found to regulate the inflammatory stage of microglia by fine-tuning the number of receptors expressed on microglia cells. In Alzheimer's disease, one of the pathological proteins involved is Tau protein, and microtubule-associated protein upon abnormal phosphorylation detaches from the microtubule and forms insoluble aggregates. Aggregated proteins have a tendency to propagate within the neurons and also become one of the causes of neuroinflammation. We hypothesize that tuning microglia towards anti-inflammatory phenotype would reduce the propagation of Tau in Alzheimer's disease.


Asunto(s)
Enfermedad de Alzheimer/patología , Encéfalo/patología , Polaridad Celular/fisiología , Grasas de la Dieta/metabolismo , Ácidos Grasos/metabolismo , Microglía/patología , Enfermedad de Alzheimer/metabolismo , Animales , Encéfalo/metabolismo , Humanos , Microglía/metabolismo , Fagocitosis/fisiología , Fosforilación , Proteínas tau/metabolismo
10.
Curr Med Sci ; 40(6): 1031-1039, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33428130

RESUMEN

rTg4510 mice are transgenic mice expressing P301L mutant tau and have been developed as an animal model of tauopathies including Alzheimer's disease (AD). Besides cognitive impairments, rTg4510 mice also show abnormal hyperactivity behavior. Cornel iridoid glycoside (CIG) is an active ingredient extracted from Cornus officinalis, a traditional Chinese herb. The purpose of the present study was to investigate the effects of CIG on the emotional disorders such as hyperactivity, and related mechanisms. The emotional hyperactivity was detected by locomotor activity test and Y maze test. Immunofluorescent and immunohistochemical analyses were conducted to measure neuron loss and phosphorylated tau. Western blotting was used to detect the expression of related proteins. The results showed that intragastric administration of CIG for 3 months decreased the hyperactivity phenotype, prevented neuronal loss, reduced tau hyperphosphorylation and aggregation in the amygdala of rTg4510 mice. Meanwhile, CIG alleviated the synaptic dysfunction by increasing the expression of N-methyl-D-aspartate receptors (NMDARs) subunits GluN1 and GluN2A and αamino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) subunits GluA1 and GluA2, and increased the level of phosphorylated Ca2+/calmodulin dependent protein kinase II α (p-CaMK IIα) in the brain of rTg4510 mice. In conclusion, CIG may have potential to treat the emotional disorders in tauopathies such as AD through reducing tau pathology and improving synaptic dysfunction.


Asunto(s)
Cornus/química , Glicósidos Iridoides/administración & dosificación , Tauopatías/tratamiento farmacológico , Proteínas tau/genética , Proteínas tau/metabolismo , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Glicósidos Iridoides/farmacología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Transgénicos , Mutación , Proteínas del Tejido Nervioso/metabolismo , Fenotipo , Fosforilación/efectos de los fármacos , Extractos Vegetales/química , Distribución Aleatoria , Receptores de N-Metil-D-Aspartato/metabolismo , Tauopatías/genética , Tauopatías/metabolismo , Tauopatías/psicología , Resultado del Tratamiento
11.
Curr Alzheimer Res ; 16(14): 1316-1331, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31902362

RESUMEN

BACKGROUND: rTg4510 mice are transgenic mice expressing P301L mutant tau and have been developed as an animal model of tauopathy including Alzheimer's Disease (AD). Cornel Iridoid Glycoside (CIG) is an active ingredient extracted from Cornus officinalis, a traditional Chinese herb. The purpose of the present study was to investigate the effects of CIG on tau pathology and underlying mechanisms using rTg4510 mice. METHODS: The cognitive functions were detected by Morris water maze and objective recognition tests. Western blotting and immunofluorescence were conducted to measure the levels of phosphorylated tau and related proteins. Serine/threonine phosphatase assay was applied to detect the activity of protein phosphatase 2A (PP2A). RESULTS: Intragastric administration of CIG for 3 months improved learning and memory abilities, prevented neuronal and synapse loss, halted brain atrophy, elevated levels of synaptic proteins, protected cytoskeleton, reduced tau hyperphosphorylation and aggregation in the brain of rTg4510 mice. In the mechanism studies, CIG increased the activity of PP2A, elevated the methylation of PP2A catalytic C (PP2Ac) at leucine 309, decreased the phosphorylation of PP2Ac at tyrosine 307, and increased protein expression of leucine carboxyl methyltransferase 1 (LCMT-1), protein tyrosine phosphatase 1B (PTP1B), and protein phosphatase 2A phosphatase activator (PTPA) in the brain of rTg4510 mice. CONCLUSION: CIG might have the potential to treat tauopathy such as AD via activating PP2A.


Asunto(s)
Encéfalo/efectos de los fármacos , Glicósidos Iridoides/farmacología , Proteína Fosfatasa 2/efectos de los fármacos , Tauopatías/metabolismo , Proteínas tau/metabolismo , Animales , Encéfalo/patología , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Fosforilación , Agregación Patológica de Proteínas/patología , Proteína Fosfatasa 2/metabolismo , Tauopatías/patología
12.
J Chem Neuroanat ; 95: 115-122, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-29051039

RESUMEN

Convolvulus pluricaulis (Shankhapushpi) has long been used as traditional herbal medicine in India as nerve tonic. We studied the neuroprotective effects of C. pluricaulis extract (aqueous) against human microtubule-associated protein tau (hMAPτ) induced neurotoxicity in Alzheimer's disease (AD) Drosophila model. We analysed the lifespan, locomotor activity, τ protein level, reactive oxygen species (ROS), lipid peroxidation (LPO), catalase (CAT), superoxide dismutase (SOD) and acetylcholinesterase (AChE) activities in 10th, 20th and 30th days old control (wild type), τ control tauopathy Drosophila reared on C. pluricaulis supplemented with regular food or regular standard food. C. pluricaulis significantly offsets hMAPτ induced early death and extends the lifespan and diminishes the level of τ protein in tauopathy Drosophila. C. pluricaulis also enhances the antioxidant enzyme activities and ameliorates the τ-induced oxidative stress and restore the depleted AChE activity in the fly model. This study provides the first evidence that supplementation of C. pluricaulis along with the regular standard food ameliorate the neurotoxic effect of hMAPτ in AD Drosophila model and also reveals that it is a potent neuroprotective agent.


Asunto(s)
Enfermedad de Alzheimer/patología , Materia Medica/farmacología , Fármacos Neuroprotectores/farmacología , Extractos Vegetales/farmacología , Animales , Convolvulus , Modelos Animales de Enfermedad , Drosophila melanogaster , Humanos , Estrés Oxidativo/efectos de los fármacos , Tauopatías/patología , Proteínas tau/genética , Proteínas tau/toxicidad
13.
Cell Rep ; 25(8): 2027-2035.e4, 2018 11 20.
Artículo en Inglés | MEDLINE | ID: mdl-30463001

RESUMEN

Tauopathies are characterized by cerebral accumulation of Tau protein aggregates that appear to spread throughout the brain via a cell-to-cell transmission process that includes secretion and uptake of pathological Tau, followed by templated misfolding of normal Tau in recipient cells. Here, we show that phosphorylated, oligomeric Tau clusters at the plasma membrane in N2A cells and is secreted in vesicle-free form in an unconventional process sensitive to changes in membrane properties, particularly cholesterol and sphingomyelin content. Cell surface heparan sulfate proteoglycans support Tau secretion, possibly by facilitating its release after membrane penetration. Notably, secretion of endogenous Tau from primary cortical neurons is mediated, at least partially, by a similar mechanism. We suggest that Tau is released from cells by an unconventional secretory mechanism that involves its phosphorylation and oligomerization and that membrane interaction may help Tau to acquire properties that allow its escape from cells directly through the plasma membrane.


Asunto(s)
Proteínas tau/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Calcio/metabolismo , Catequina/análogos & derivados , Catequina/farmacología , Línea Celular , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Membrana Celular/ultraestructura , Heparina/análogos & derivados , Heparina/metabolismo , Lípidos/química , Ratones , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Proteoglicanos/metabolismo , Ratas , Proteínas tau/ultraestructura
14.
Expert Opin Investig Drugs ; 27(4): 349-361, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29602288

RESUMEN

INTRODUCTION: Our understanding of the pathological basis of progressive supranuclear palsy (PSP), as the most common atypical parkinsonian syndrome, has greatly increased in recent years and a number of disease-modifying therapies are under evaluation as a result of these advances. AREAS COVERED: In this review, we discuss disease-modifying therapeutic options which are currently under evaluation or have been evaluated in preclinical or clinical trials based on their targeted pathophysiologic process. The pathophysiologic mechanisms are broadly divided into three main categories: genetic mechanisms, abnormal post-translational modifications of tau protein, and transcellular tau spread. EXPERT OPINION: Once the best therapeutic approaches are identified, it is likely that some combination of interventions will need to be evaluated, but this will take time. It is critical to treat patients at early stages, and development of the Movement Disorder Society PSP diagnostic criteria is an important step in this direction. In addition, development of biological biomarkers such as tau PET and further refinement of tau ligands may help both diagnose early and measure disease progression. In the meantime, a comprehensive, personalized interdisciplinary approach to this disease is absolutely necessary.


Asunto(s)
Diseño de Fármacos , Drogas en Investigación/uso terapéutico , Parálisis Supranuclear Progresiva/tratamiento farmacológico , Animales , Biomarcadores/metabolismo , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Progresión de la Enfermedad , Evaluación Preclínica de Medicamentos , Drogas en Investigación/farmacología , Humanos , Procesamiento Proteico-Postraduccional , Parálisis Supranuclear Progresiva/diagnóstico , Parálisis Supranuclear Progresiva/fisiopatología , Proteínas tau/metabolismo
15.
J Prev Alzheimers Dis ; 4(4): 236-241, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29181488

RESUMEN

Tau neurofibrillary tangles are found in the brains of patients suffering from Alzheimer's disease and other tauopathies. The progressive spreading of tau pathology from one brain region to the next is believed to be caused by extracellular transsynaptic transmission of misfolded tau between neurons. Preclinical studies have shown that antibodies against tau can prevent this transfer of misfolded tau between cells. Thus, antibodies against tau have the potential to stop or slow the progression of tau pathology observed in human tauopathies. To test this hypothesis, a humanized anti-tau antibody (ABBV-8E12) was developed and a phase 1 clinical trial of this antibody has been completed. The double-blind, placebo-controlled phase 1 study tested single doses of ABBV-8E12 ranging from 2.5 to 50 mg/kg in 30 patients with progressive supranuclear palsy (PSP). ABBV-8E12 was found to have an acceptable safety profile with no clinically concerning trends in the number or severity of adverse events between the placebo and dosed groups. Pharmacokinetic modelling showed that the antibody has a plasma half-life and cerebrospinal fluid:plasma ratio consistent with other humanized antibodies, and there were no signs of immunogenicity against ABBV-8E12. Based on the acceptable safety and tolerability profile of single doses of ABBV-8E12, AbbVie is currently enrolling patients into two phase 2 clinical trials to assess efficacy and safety of multiple doses of ABBV-8E12 in patients with early Alzheimer's disease or PSP.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Factores Inmunológicos/uso terapéutico , Tauopatías/terapia , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacocinética , Método Doble Ciego , Evaluación Preclínica de Medicamentos , Humanos , Factores Inmunológicos/efectos adversos , Factores Inmunológicos/farmacocinética , Inmunoterapia , Modelos Biológicos , Tauopatías/sangre , Tauopatías/líquido cefalorraquídeo
16.
Biosens Bioelectron ; 88: 78-84, 2017 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-27506337

RESUMEN

Over the last decades, countless bioelectronic monitoring systems were developed for the analysis of cells as well as complex tissues. Most studies addressed the sensitivity and specificity of the bioelectronic detection method in comparison to classical molecular biological assays. In contrast, the up scaling as a prerequisite for the practical application of these novel bioelectronic monitoring systems is mostly only discussed theoretically. In this context, we developed a novel 384-multiwell microelectrode array (MMEA) based measurement system for the sensitive label-free real-time monitoring of neurodegenerative processes by impedance spectroscopy. With respect to the needs of productive screening systems for robust and reproducible measurements on high numbers of plates, we focused on reducing the critical contacting of more than 400 electrodes for a 384-MMEA. Therefore, we introduced an on top array of immersive counter electrodes that are individually addressed by a multiplexer and connected all measurement electrodes on the 384-MMEA to a single contact point. More strikingly, our novel approach provided a comparable signal stability and sensitivity similar to an array with integrated counter electrodes. Next, we optimized a SH-SY5Y cell based tauopathy model by introducing a novel 5-fold Tau mutation eliminating the need of artificial tauopathy induction. In combination with our novel 384-MMEA based measurement system, the concentration and time dependent neuroregenerative effect of the kinase inhibitor SRN-003-556 could be quantitatively monitored. Thus, our novel screening system could be a useful tool to identify and develop potential novel therapeutics in the field of Tau-related neurodegenerative diseases.


Asunto(s)
Espectroscopía Dieléctrica/instrumentación , Tauopatías/diagnóstico , Proteínas tau/análisis , Carbazoles/farmacología , Línea Celular , Espectroscopía Dieléctrica/métodos , Evaluación Preclínica de Medicamentos/instrumentación , Evaluación Preclínica de Medicamentos/métodos , Diseño de Equipo , Humanos , Microelectrodos , Tauopatías/tratamiento farmacológico
17.
J Neurochem ; 139(4): 624-639, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27569447

RESUMEN

In the pathogenesis of tauopathies, genetic and environmental factors have been identified. While familial clustering led to the identification of mutations in MAPT encoding the microtubule-associated protein tau, the high incidence of a sporadic tauopathy endemic in Guadeloupe was linked to the plant-derived mitochondrial complex I inhibitor annonacin. The interaction of both factors was studied in the present work in a realistic paradigm over a period of 12 months. Mice over-expressing either human wild-type tau or R406W mutant tau as well as non-transgenic mice received either regular drinking water or commercially available tropical fruit juice made of soursop (Annona muricata L.) as dietary source of neurotoxins. HPLC-MS analysis of this juice identified several Annonaceous acetogenins, mainly annonacin (16.2 mg/L), and 41 isoquinoline alkaloids (18.0 mg/L, mainly asimilobine and reticuline). After 12 month of juice consumption, several brain regions showed an increased number of neurons with phosphorylated tau in the somatodendritic compartment of R406W mice and, to a much lesser extent, of non-transgenic mice and mice over-expressing human wild-type tau. Moreover, juice drinking was associated with a reduction in synaptophysin immunoreactivity, as well as an increase in 3-nitrotyrosine (3NT) reactivity in all three genotypes. The increase in 3NT suggests that Annona muricata juice promotes the generation of reactive nitrogen species. This study provides first experimental evidence that long-lasting oral ingestion of a widely consumed environmental factor can induce somatodendritic accumulation of hyperphosphorylated tau in mice expressing rodent or human wild-type tau, and can accelerate tau pathology in R406W-MAPT transgenic mice.


Asunto(s)
Annona , Encéfalo/metabolismo , Jugos de Frutas y Vegetales , Extractos Vegetales/administración & dosificación , Proteínas tau/biosíntesis , Animales , Annona/efectos adversos , Encéfalo/efectos de los fármacos , Línea Celular , Jugos de Frutas y Vegetales/efectos adversos , Humanos , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Transgénicos , Fosforilación/efectos de los fármacos , Fosforilación/fisiología , Extractos Vegetales/efectos adversos , Distribución Aleatoria , Proteínas tau/genética
18.
Biochem Biophys Res Commun ; 477(2): 283-9, 2016 08 19.
Artículo en Inglés | MEDLINE | ID: mdl-27301640

RESUMEN

Tau plays important roles in the assembly and stabilization of the microtubule structure to facilitate axonal transport in mammalian brain. The intracellular tau aggregates to form paired helical filaments leading to neurodegenerative disorders, collectively called tauopathies. In our previous report, we established a zebrafish model to express tau-GFP to induce neuronal death, which could be directly traced in vivo. Recently, we used this model to screen 400 herbal extracts and found 45 of them to be effective on reducing tau-GFP-induced neuronal death. One of the effective herbal extracts is the Tripterygium wilfordii stem extract. HPLC analysis and functional assay demonstrated that epicatechin (EC) is the major compound of Tripterygium wilfordii stem extract to decrease the neurotoxicity induced by tau-GFP. Using a luciferase reporter assay in the zebrafish, we confirmed that EC could activate Nrf2-dependent antioxidant responses to significantly increase the ARE-controlled expression of luciferase reporter gene. These data suggest that EC from the Tripterygium wilfordii stem extract could diminish tau-GFP-induced neuronal death through the activation of Nrf2.


Asunto(s)
Catequina/administración & dosificación , Factor 2 Relacionado con NF-E2/metabolismo , Neuronas/metabolismo , Neuronas/patología , Tripterygium/química , Proteínas de Pez Cebra/metabolismo , Proteínas tau/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Embrión no Mamífero/efectos de los fármacos , Embrión no Mamífero/metabolismo , Embrión no Mamífero/patología , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/administración & dosificación , Extractos Vegetales/administración & dosificación , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Pez Cebra , Proteínas tau/genética
19.
Methods Mol Biol ; 1438: 311-47, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27150098

RESUMEN

The major symptom of Alzheimer's disease is dementia progressing with age. Its clinical diagnosis is preceded by a long prodromal period of brain pathology that encompasses both formation of extracellular amyloid and intraneuronal tau deposits in the brain and widespread neuronal death. At present, familial cases of dementia provide the most promising foundation for modeling neurodegenerative tauopathies, a group of heterogeneous disorders characterized by prominent intracellular accumulation of hyperphosphorylated tau protein. In this chapter, we describe major behavioral hallmarks of tauopathies, briefly outline the genetics underlying familial cases, and discuss the arising implications for modeling the disease in transgenic mouse systems. The selection of tests performed to evaluate the phenotype of a model should be guided by the key behavioral hallmarks that characterize human disorder and their homology to mouse cognitive systems. We attempt to provide general guidelines and establish criteria for modeling dementia in a mouse; however, interpretations of obtained results should avoid a reductionist "one gene, one disease" explanation of model characteristics. Rather, the focus should be directed to the question of how the mouse genome can cope with the over-expression of the protein coded by transgene(s). While each model is valuable within its own constraints and the experiments performed are guided by specific hypotheses, we seek to expand upon their methodology by offering guidance spanning from issues of mouse husbandry to choices of behavioral tests and routes of drug administration that might increase the external validity of studies and consequently optimize the translational aspect of preclinical research.


Asunto(s)
Tauopatías/patología , Tauopatías/psicología , Animales , Conducta Animal , Encéfalo/patología , Modelos Animales de Enfermedad , Vías de Administración de Medicamentos , Evaluación Preclínica de Medicamentos , Guías como Asunto , Humanos , Ratones , Ratones Transgénicos , Pruebas Neuropsicológicas
20.
Drug Des Devel Ther ; 10: 885-96, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27013866

RESUMEN

BACKGROUND: Alzheimer's disease (AD) and several neurodegenerative disorders known as tauopathies are characterized by misfolding and aggregation of tau protein. Although several studies have suggested the potential of traditional Chinese medicine (TCM) as treatment for neurodegenerative diseases, the role of TCM in treating AD and tauopathies have not been well explored. MATERIALS AND METHODS: Tau protein was coupled to the DsRed fluorophore by fusing a pro-aggregation mutant of repeat domain of tau (ΔK280 tauRD) with DsRed. The ΔK280 tauRD-DsRed fusion gene was then used to generate Tet-On 293 and SH-SY5Y cell clones as platforms to test the efficacy of 39 aqueous extracts of TCM in reducing tau misfolding and in neuroprotection. RESULTS: Seven TCM extracts demonstrated a significant reduction in tau misfolding and reactive oxidative species with low cytotoxicity in the ΔK280 tauRD-DsRed 293 cell model. Glycyrrhiza inflata and Panax ginseng also demonstrated the potential to improve neurite outgrowth in the ΔK280 tauRD-DsRed SH-SY5Y neuronal cell model. G. inflata further rescued the upregulation of ERN2 (pro-apoptotic) and downregulation of unfolded-protein-response-mediated chaperones ERP44, DNAJC3, and SERP1 in ΔK280 tauRD-DsRed 293 cells. CONCLUSION: This in vitro study provides evidence that G. inflata may be a novel therapeutic for AD and tauopathies. Future applications of G. inflata on animal models of AD and tauopathies are warranted to corroborate its effect of reducing misfolding and potential disease modification.


Asunto(s)
Enfermedad de Alzheimer/patología , Medicamentos Herbarios Chinos/farmacología , Glycyrrhiza/química , Chaperonas Moleculares/metabolismo , Neuronas/efectos de los fármacos , Desplegamiento Proteico/efectos de los fármacos , Respuesta de Proteína Desplegada/fisiología , Proteínas tau/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/química , Células HEK293 , Humanos , Medicina Tradicional China , Modelos Biológicos , Neuronas/metabolismo , Extractos Vegetales/química , Extractos Vegetales/farmacología , Relación Estructura-Actividad , Respuesta de Proteína Desplegada/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Agua/química , Proteínas tau/química
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