Agonistes de neurotrofines com a teràpia neuroprotectora per la Esclerosi Múltiple

Les neurotrofines son factors tròfics que poden induir la supervivencia, la diferenciació i el creixement de les neurones i aquesta és la principal raó per la qual les estudiem en el context de les malalties neurológiques. Les propietats nombrades son crucials per a la cerca d’efectes funcionals pel que fa a tractaments de malalties neurológiques. Avui en dia. donada la seva activitat neuroprotectora, s’ha intentat l’administració extena de neurotrofines com una terapia per diverses enfermetats cerebrals, pero fins ara han tingut poc o cap resultat donada la inhabilitat d’aquestes molècules per creuar la barrera hematoencefàlica i pels seus efectes secondaris, com ara el dolor neuroilogic. Per això, l’aplicació de petites molècules similars a les neurotrofines es considerada com unapossible sol•lució com un possible tractament neuroprotector amb el cervell com a diana. L’objectiu principal d’aquest projecte és testar l’eficacia d’un compost replicant de la neurotrofina pel tractament de algunes enfermetats neurològiques i per a estudiar el mecanisme d’acció d’aquesta molècula. Els resultats obtinguts fins al moment mostren que hem desenvolupat e identificat un compost replicant de la neurotrofina (G79) que manté la seva capacitat com a factor de creixement nerviós (NGF) en un assaig funcional d’NGF (diferenciació i tests de supervivència). A més a més, hem obtingut una proba de concepte per a la eficacia d’aquest compost com un agent terapèutic en diversos models in vivo e in vitro d’Esclerosi Múltiple, glaucoma, enfermetat de Parkinson y Esclerosi Lateral Amiotrófica. En conclusió, els resultats obtinguts durant aquests dos anys suggereixen que la molècula replicant d’NGF G79 és un bon candidat per a ser desenvolutat com a part d’una estratégica terapeutica la diferenciació neuronal, promou la supervivència, activa la fosforilització de TrkA i TrkB, vies de senyalització específiques de la neurotrofina. Aquesta molècula ademés pot creuar la barrera hematoencefàlica per vies de transport actiu, millora el score clínic en animals infectats per Encefalomielitis Autoinmune Experimental, protegeix les cèlules gangliars retinals en el model in vivo de Glaucoma, promou la supervivència de les cèlules en els models in vitro de l’enfermetat de Parkinson i en ELA. En resum, els nostres resultats sugereixen que les molècules replicants de neurotrofina poden desenvoluparse com part d’una estratègia terapéutica neuroprotectora.

Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase

There is no treatment for the neurodegenerative disorder Huntington disease (HD). Cystamine is a candidate drug; however, the mechanisms by which it operates remain unclear. We show here that cystamine increases levels of the heat shock DnaJ-containing protein 1b (HSJ1b) that are low in HD patients. HSJ1b inhibits polyQ-huntingtin¿induced death of striatal neurons and neuronal dysfunction in Caenorhabditis elegans. This neuroprotective effect involves stimulation of the secretory pathway through formation of clathrin-coated vesicles containing brain-derived neurotrophic factor (BDNF). Cystamine increases BDNF secretion from the Golgi region that is blocked by reducing HSJ1b levels or by overexpressing transglutaminase. We demonstrate that cysteamine, the FDA-approved reduced form of cystamine, is neuroprotective in HD mice by increasing BDNF levels in brain. Finally, cysteamine increases serum levels of BDNF in mouse and primate models of HD. Therefore, cysteamine is a potential treatment for HD, and serum BDNF levels can be used as a biomarker for drug efficacy.

Calcium homeostasis in the central nervous system: adaptation to neurodegeneration.

Here we review the results of our recent studies on neurodegeneration together with data on cerebral calcium precipitation in animal models and humans. A model that integrates the diversity of mechanisms involved in neurodegeneration is presented and discussed based on the functional relevance of calcium precipitation.

Molecular Mechanisms of Acute Brain Injury and Ensuing Neurodegeneration

Injury to the central nervous system (CNS), including stroke, traumatic brain injury andspinal cord injury, cause devastating and irreversible damage and loss of function. Forexample, stroke affects very large patient populations, results in major suffering for the patients and their relatives, and involves a significant cost to society. CNS damage implies disruption of the intricate internal circuits involved in cognition, the sensory-motor functions, and other important functions. There are currently no treatments available to properly restore such lost functions. New therapeutic proposals will emerge from an understanding of the interdependence of molecular and cellular responses to CNS injury, in particular the inhibitory mechanisms that block regeneration and those that enhanceneuronal plasticity...

A nuclear defect in the 4p16 region predisposes to multiple mitochondrial DNA deletions in families with Wolfram syndrome.

Wolfram syndrome is a progressive neurodegenerative disorder transmitted in an autosomal recessive mode. We report two Wolfram syndrome families harboring multiple deletions of mitochondrial DNA. The deletions reached percentages as high as 85-90% in affected tissues such as the central nervous system of one patient, while in other tissues from the same patient and from other members of the family, the percentages of deleted mitochondrial DNA genomes were only 1-10%. Recently, a Wolfram syndrome gene has been linked to markers on 4p16. In both families linkage between the disease locus and 4p16 markers gave a maximum multipoint lod score of 3.79 at theta = 0 (Pi<0.03) with respect to D4S431. In these families, the syndrome was caused by mutations in this nucleus-encoded gene which deleteriously interacts with the mitochondrial genome. This is the first evidence of the implication of both genomes in a recessive disease.

A nuclear defect in the 4p16 region predisposes to multiple mitochondrial DNA deletions in families with Wolfram syndrome.

Wolfram syndrome is a progressive neurodegenerative disorder transmitted in an autosomal recessive mode. We report two Wolfram syndrome families harboring multiple deletions of mitochondrial DNA. The deletions reached percentages as high as 85-90% in affected tissues such as the central nervous system of one patient, while in other tissues from the same patient and from other members of the family, the percentages of deleted mitochondrial DNA genomes were only 1-10%. Recently, a Wolfram syndrome gene has been linked to markers on 4p16. In both families linkage between the disease locus and 4p16 markers gave a maximum multipoint lod score of 3.79 at theta = 0 (Pi<0.03) with respect to D4S431. In these families, the syndrome was caused by mutations in this nucleus-encoded gene which deleteriously interacts with the mitochondrial genome. This is the first evidence of the implication of both genomes in a recessive disease.

Aberrant repair and fibrosis development in skeletal muscle

The repair process of damaged tissue involves the coordinated activities of several cell types in response to local and systemic signals. Following acute tissue injury, infiltrating inflammatory cells and resident stem cells orchestrate their activities to restore tissue homeostasis. However, during chronic tissue damage, such as in muscular dystrophies, the inflammatory-cell infiltration and fibroblast activation persists, while the reparative capacity of stem cells (satellite cells) is attenuated. Abnormal dystrophic muscle repair and its end stage, fibrosis, represent the final common pathway of virtually all chronic neurodegenerative muscular diseases. As our understanding of the pathogenesis of muscle fibrosis has progressed, it has become evident that the muscle provides a useful model for the regulation of tissue repair by the local microenvironment, showing interplay among muscle-specific stem cells, inflammatory cells, fibroblasts and extracellular matrix components of the mammalian wound-healing response. This article reviews the emerging findings of the mechanisms that underlie normal versus aberrant muscle-tissue repair.

Estudi del procés de neurodegeneració

Les anomenades malalties neurodegeneratives tenen una simptomatologia i unes manifestacions clíniques molt diferents entre elles. No obstant, totes elles convergeixen en el mateix procés final, la neurodegeneració, que es manifestarà en diferents localitzacions o tipus cel·lulars del sistema nerviós. Nosaltres, plantegem la hipòtesi de que els processos moleculars i cel·lulars subjacents a la neurodegeneració són comuns per totes elles. Després de dur a terme un procés de selecció, es decideix treballar amb la malaltia de Parkinson, la d’Alzheimer, l’Esclerosi lateral amiotròfica i l’esclerosi múltiple. Hem pogut determinar que hi ha set processos moleculars o cel·lulars que estan associats al procés de neurodegeneració i que són comuns a totes elles. Havent-les estudiat per separat s’observa que el procés de neurodegeneració consisteix en una fallada en cadena de diferents sistemes moleculars i cel·lulars que tenen com a punt d’origen l’estrès oxidatiu. A aquest estrès s’hi pot arribar de diferents maneres. Una d’elles és l’exposició excessiva a certs metalls, que provoca la pèrdua dels sistemes antioxidants cel·lulars. Degut a això, els mitocondris reben un impacte oxidatiu massa gran i comencen a fallar. El fet que aquest orgànul actuï com a tampó del calci intracel·lular en provoca la seva desregulació, alterant d’aquesta manera el senyal nerviós. En resposta a l’estrès oxidatiu i tèrmic que genera la disfunció mitocondrial, s’activen les Proteïnes de Xoc Tèrmic (HSP) que actuant de citocines i presentadores d’antígens, inicien la resposta immunològica contra les cèl·lules danyades. Paral·lelament, s’observa un increment de la permeabilitat de la barrera hematoencefàlica degut a la pèrdua de les adhesions cel·lulars estretes per l’alta presència d’espècies reactives. Com a conseqüència de l’afebliment o el trencament de la barrera hematoencefàlica, es pot produir una entrada al SNC de diferents substàncies neurotòxiques i de cèl·lules del sistema immunitàri que, en condicions normals tenen l’accés restringit. Juntament amb aquestes cèl·lules immunològiques, també s’activen les cèl·lules del sistema immunitari innat residents al cervell, la micròglia, i totes elles secreten citocines proinflamatòries que contribueixen al procés de neurodegeneració. Nosaltres presentem els mecanismes pels quals aquesta inflamació, lluny d’atenuar-se, es cronifica per l’acció de certs bucles de retroalimentació positiva. Les diferents peculiaritats de cada malaltia contribueixen en aquest procés de diferents maneres, com és el cas dels pèptids β-amilides en la malaltia d’Alzheimer, l’α-sinucleina en el Parkinson, la superòxid dismutasa (SOD) en l’esclerosi lateral amiotròfica, o l’infiltració de leucòcits al cervell degut a la resposta autoimmune de l’esclerosi múltiple.Deixant de banda aquestes diferències, si el procés és comú entre totes elles, l’estudi a fons d’aquest procés hauria de poder permetre identificar dianes tarapèutiques que siguin comunes per les quatre malalties.

Depression-like behavior is dependent on age in male SAMP8 mice

Aging is associated with an increased risk of depression in humans. To elucidate the underlying mechanisms of depression and its dependence on aging, here we study signs of depression in male SAMP8 mice. For this purpose, we used the forced swimming test (FST). The total floating time in the FST was greater in SAMP8 than in SAMR1 mice at 9 months of age; however, this difference was not observed in 12-month-old mice, when both strains are considered elderly. Of the two strains, only the SAMP8 animals responded to imipramine treatment. We also applied the dexamethasone suppression test (DST) and studied changes in the dopamine and serotonin (5-HT) uptake systems, the 5-HT2a/2c receptor density in the cortex, and levels of TPH2. The DST showed a significant difference between SAMR1 and SAMP8 mice at old age. SAMP8 exhibits an increase in 5-HT transporter density, with slight changes in 5-HT2a/2c receptor density. In conclusion, SAMP8 mice presented depression-like behavior that is dependent on senescence process, because it differs from SAMR1, senescence resistant strain.

Dietary resveratrol prevents alzheimer's markers and increases life span in SAMP8

Resveratrol is a polyphenol that is mainly found in grapes and red wine and has been reported to be a caloric restriction (CR) mimetic driven by Sirtuin 1 (SIRT1) activation. Resveratrol increases metabolic rate, insulin sensitivity, mitochondrial biogenesis and physical endurance, and reduces fat accumulation in mice. In addition, resveratrol may be a powerful agent to prevent age-associated neurodegeneration and to improve cognitive deficits in Alzheimer's disease (AD). Moreover, different findings support the view that longevity in mice could be promoted by CR. In this study, we examined the role of dietary resveratrol in SAMP8 mice, a model of age-related AD. We found that resveratrol supplements increased mean life expectancy and maximal life span in SAMP8 and in their control, the related strain SAMR1. In addition, we examined the resveratrol-mediated neuroprotective effects on several specific hallmarks of AD. We found that long-term dietary resveratrol activates AMPK pathways and pro-survival routes such as SIRT1 in vivo. It also reduces cognitive impairment and has a neuroprotective role, decreasing the amyloid burden and reducing tau hyperphosphorylation.

Dietary resveratrol prevents alzheimer's markers and increases life span in SAMP8

Resveratrol is a polyphenol that is mainly found in grapes and red wine and has been reported to be a caloric restriction (CR) mimetic driven by Sirtuin 1 (SIRT1) activation. Resveratrol increases metabolic rate, insulin sensitivity, mitochondrial biogenesis and physical endurance, and reduces fat accumulation in mice. In addition, resveratrol may be a powerful agent to prevent age-associated neurodegeneration and to improve cognitive deficits in Alzheimer's disease (AD). Moreover, different findings support the view that longevity in mice could be promoted by CR. In this study, we examined the role of dietary resveratrol in SAMP8 mice, a model of age-related AD. We found that resveratrol supplements increased mean life expectancy and maximal life span in SAMP8 and in their control, the related strain SAMR1. In addition, we examined the resveratrol-mediated neuroprotective effects on several specific hallmarks of AD. We found that long-term dietary resveratrol activates AMPK pathways and pro-survival routes such as SIRT1 in vivo. It also reduces cognitive impairment and has a neuroprotective role, decreasing the amyloid burden and reducing tau hyperphosphorylation.

Dietary resveratrol prevents alzheimer's markers and increases life span in SAMP8

Resveratrol is a polyphenol that is mainly found in grapes and red wine and has been reported to be a caloric restriction (CR) mimetic driven by Sirtuin 1 (SIRT1) activation. Resveratrol increases metabolic rate, insulin sensitivity, mitochondrial biogenesis and physical endurance, and reduces fat accumulation in mice. In addition, resveratrol may be a powerful agent to prevent age-associated neurodegeneration and to improve cognitive deficits in Alzheimer's disease (AD). Moreover, different findings support the view that longevity in mice could be promoted by CR. In this study, we examined the role of dietary resveratrol in SAMP8 mice, a model of age-related AD. We found that resveratrol supplements increased mean life expectancy and maximal life span in SAMP8 and in their control, the related strain SAMR1. In addition, we examined the resveratrol-mediated neuroprotective effects on several specific hallmarks of AD. We found that long-term dietary resveratrol activates AMPK pathways and pro-survival routes such as SIRT1 in vivo. It also reduces cognitive impairment and has a neuroprotective role, decreasing the amyloid burden and reducing tau hyperphosphorylation.

Depression-like behavior is dependent on age in male SAMP8 mice

Aging is associated with an increased risk of depression in humans. To elucidate the underlying mechanisms of depression and its dependence on aging, here we study signs of depression in male SAMP8 mice. For this purpose, we used the forced swimming test (FST). The total floating time in the FST was greater in SAMP8 than in SAMR1 mice at 9 months of age; however, this difference was not observed in 12-month-old mice, when both strains are considered elderly. Of the two strains, only the SAMP8 animals responded to imipramine treatment. We also applied the dexamethasone suppression test (DST) and studied changes in the dopamine and serotonin (5-HT) uptake systems, the 5-HT2a/2c receptor density in the cortex, and levels of TPH2. The DST showed a significant difference between SAMR1 and SAMP8 mice at old age. SAMP8 exhibits an increase in 5-HT transporter density, with slight changes in 5-HT2a/2c receptor density. In conclusion, SAMP8 mice presented depression-like behavior that is dependent on senescence process, because it differs from SAMR1, senescence resistant strain.

Vigilar les calories per poder mantenir el cervell jove

Els excessos a la taula també influeixen en els mecanismes que expliquen el desenvolupament de les malalties neurodegeneratives

CX3CR1 is a modifying gene of survival and progression in Amyotrophic Lateral Sclerosis

The objective of this study was to investigate the association of functional variants of the human CX3CR1 gene (Fractalkine receptor) with the risk of Amyotrophic Lateral Sclerosis disease (ALS), the survival and the progression rate of the disease symptoms in a Spanish ALS cohort. 187 ALS patients (142sporadic [sALS] and 45 familial) and 378 controls were recruited. We investigated CX3CR1 V249I (rs3732379) and T280M (rs3732378) genotypes and their haplotypes as predictors of survival, the progression rate of the symptoms (as measured by ALSFRS-R and FVC decline) and the risk of suffering ALS disease. The results indicated that sALS patients with CX3CR1 249I/I or 249V/I genotypes presented a shorter survival time (42.21±4.82) than patients with 249V/V genotype (67.48±7.28; diff=-25.27 months 95%CI [-42.09,-8.45]; p=0.003). The survival time was shorter in sALS patients with spinal topography and CX3CR1 249I alleles (diff -29.78 months; 95%CI [-49.42,-10.14]; p=0.003). The same effects were also observed in the spinal sALS patients with 249I-280M haplotype (diff=-27.23 months; 95%CI [-49.83,-4.64]; p=0.018). In the sALS group, the CX3CR1 249I variant was associated with a faster progression of the disease symptoms (OR= 2.32; 95IC%[1.24, 4.33]; p=0.007). There was no evidence for association of these two CX3CR1 variants with ALS disease risk. The association evidenced herein is clinically relevant and indicates that CX3CR1 could be a disease-modifying gene in sALS. The progression rate of the disease"s symptoms and the survival time is affected in patients with one or two copies of the CX3CR1 249I allele. The CX3CR1 is the most potent ALS survival genetic factor reported to date. These results reinforce the role of the immune system in ALS pathogenesis.