Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 22
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
Dev Neurosci ; 44(1): 23-38, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34852343

RESUMO

Down syndrome (DS), which is due to triplication of chromosome 21, is constantly associated with intellectual disability (ID). ID can be ascribed to both neurogenesis impairment and dendritic pathology. These defects are replicated in the Ts65Dn mouse, a widely used model of DS. While neurogenesis impairment in DS is a fetal event, dendritic pathology occurs after the first postnatal months. Neurogenesis alterations across the life span have been extensively studied in the Ts65Dn mouse. In contrast, there is scarce information regarding dendritic alterations at early life stages in this and other models, although there is evidence for dendritic alterations in adult mouse models. Thus, the goal of the current study was to establish whether dendritic alterations are already present in the neonatal period in Ts65Dn mice. In Golgi-stained brains, we quantified the dendritic arbors of layer II/III pyramidal neurons in the frontal cortex of Ts65Dn mice aged 2 (P2) and 8 (P8) days and their euploid littermates. In P2 Ts65Dn mice, we found a moderate hypotrophy of the apical and collateral dendrites but a patent hypotrophy of the basal dendrites. In P8 Ts65Dn mice, the distalmost apical branches were missing or reduced in number, but there were no alterations in the collateral and basal dendrites. No genotype effects were detected on either somatic or dendritic spine density. This study shows dendritic branching defects that mainly involve the basal domain in P2 Ts65Dn mice and the apical but not the other domains in P8 Ts65Dn mice. This suggests that dendritic defects may be related to dendritic compartment and age. The lack of a severe dendritic pathology in Ts65Dn pups is reminiscent of the delayed appearance of patent dendritic alterations in newborns with DS. This similarly highlights the usefulness of the Ts65Dn model for the study of the mechanisms underlying dendritic alterations in DS and the design of possible therapeutic interventions.


Assuntos
Síndrome de Down , Neocórtex , Animais , Modelos Animais de Doenças , Síndrome de Down/tratamento farmacológico , Síndrome de Down/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurogênese , Células Piramidais/patologia
2.
Crit Rev Food Sci Nutr ; 62(1): 13-50, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-32914634

RESUMO

Flavonoids have long been known to exert benefits in various health problems. Among them, the BDNF mimetic 7,8-Dihydroxyflavone (7,8-DHF) is emerging as a potential treatment for a constellation of brain and body pathologies. During the past 10 years, more than 180 preclinical studies have explored the efficacy of 7,8-DHF in animal models of different pathologies. The current review intends to be an exhaustive survey of these studies. By providing detailed information on the rationale of the experimental design and outcome of treatment, we will give the reader tools to critically interpret the achievement obtained so far. If we put together each individual piece of this complex mosaic, a picture emerges that is full of promise regarding the potential usefulness of 7,8-DHF for human treatment. Much has been done so far and we believe that the time is now ripe to move from the bench to the bedside, in order to establish whether supplementation with 7,8-DHF may serve as therapy or, at least, as adjuvant for the treatment of pathologies affecting brain and body functioning.


Assuntos
Encefalopatias , Flavonas , Animais , Encefalopatias/tratamento farmacológico , Flavonas/farmacologia , Flavonoides , Humanos , Receptor trkB
3.
Hippocampus ; 31(4): 435-447, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33464704

RESUMO

Down syndrome (DS), a genetic condition caused by triplication of chromosome 21, is characterized by alterations in various cognitive domains, including hippocampus-dependent memory functions, starting from early life stages. The major causes of intellectual disability in DS are prenatal neurogenesis alterations followed by impairment of dendritic development in early infancy. While there is evidence that the Ts65Dn mouse, the most widely used model of DS, exhibits dendritic alterations in adulthood, no studies are available regarding the onset of dendritic pathology. The goal of the current study was to establish whether this model exhibits early dendritic alterations in the hippocampus, a region whose function is severely damaged in DS. To this purpose, in Golgi-stained brains, we evaluated the dendritic arborization and dendritic spines of the granule cells of the hippocampal dentate gyrus in Ts65Dn mice aged 8 (P8) and 15 (P15) days. While P15 Ts65Dn mice exhibited a notably hypotrophic dendritic arbor and a reduced spine density, P8 mice exhibited a moderate reduction in the number of dendritic ramifications and no differences in spine density in comparison with their euploid counterparts. Both in P8 and P15 mice, spines were longer and had a longer neck, suggesting possible alterations in synaptic function. Moreover, P8 and P15 Ts65Dn mice had more thin spines and fewer stubby spines in comparison with euploid mice. Our study provides novel evidence on the onset of dendritic pathology, one of the causes of intellectual disability in DS, showing that it is already detectable in the dentate gyrus of Ts65Dn pups. This evidence strengthens the suitability of this model of DS as a tool to study dendritic pathology in DS and to test the efficacy of early therapeutic interventions aimed at ameliorating hippocampal development and, therefore, memory functions in children with DS.


Assuntos
Síndrome de Down , Animais , Modelos Animais de Doenças , Hipocampo/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurogênese
4.
Neurobiol Dis ; 140: 104874, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32325119

RESUMO

Down syndrome (DS), a neurodevelopmental disorder caused by triplication of chromosome 21, is characterized by intellectual disability. In DS, defective neurogenesis causes an overall reduction in the number of neurons populating the brain and defective neuron maturation causes dendritic hypotrophy and reduction in the density of dendritic spines. No effective therapy currently exists for the improvement of brain development in individuals with DS. Drug repurposing is a strategy for identifying new medical use for approved drugs. A drug screening campaign showed that the ß2-adrenergic receptor (ß2-AR) agonists clenbuterol hydrochloride (CLEN) and salmeterol xinafoate (SALM) increase the proliferation rate of neural progenitor cells from the Ts65Dn model of DS. The goal of the current study was to establish their efficacy in vivo, in the Ts65Dn model. We found that, at variance with the in vitro experiments, treatment with CLEN or SALM did not restore neurogenesis in the hippocampus of Ts65Dn mice treated during the postnatal (P) period P3-P15. In Ts65Dn mice treated with CLEN or SALM, however, dendritic spine density and dendritic arborization of the hippocampal granule cells were restored and the lowest dose tested here (0.01 mg/kg/day) was sufficient to elicit these effects. CLEN and SALM are used in children as therapy for asthma and, importantly, they pass the blood-brain barrier. Our study suggests that treatment with these ß2-AR agonists may be a therapy of choice in order to correct dendritic development in DS but is not suitable to rescue neurogenesis.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Clembuterol/uso terapêutico , Giro Denteado/efeitos dos fármacos , Síndrome de Down/tratamento farmacológico , Xinafoato de Salmeterol/uso terapêutico , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Feminino , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Transgênicos , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos
5.
Neurobiol Dis ; 129: 44-55, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31085229

RESUMO

Down syndrome (DS), a genetic condition due to triplication of chromosome 21, is characterized by reduced proliferation of neural progenitor cells (NPCs) starting from early life stages. This defect is worsened by a reduction of neuronogenesis (accompanied by an increase in astrogliogenesis) and dendritic spine atrophy. Since this triad of defects underlies intellectual disability, it seems important to establish whether it is possible to pharmacologically correct these alterations. In this study, we exploited the Ts65Dn mouse model of DS in order to obtain an answer to this question. In the framework of an in vitro drug-screening campaign of FDA/EMA-approved drugs, we found that the immunosuppressant cyclosporine A (CSA) restored proliferation, acquisition of a neuronal phenotype, and maturation of neural progenitor cells (NPCs) from the subventricular zone (SVZ) of the lateral ventricle of Ts65Dn mice. Based on these findings, we treated Ts65Dn mice with CSA in the postnatal period P3-P15. We found that treatment fully restored NPC proliferation in the SVZ and in the subgranular zone of the hippocampal dentate gyrus, and total number of hippocampal granule cells. Moreover, CSA enhanced development of dendritic spines on the dendritic arbor of the granule cells whose density even surpassed that of euploid mice. In hippocampal homogenates from Ts65Dn mice, we found that CSA normalized the excessive levels of p21, a key determinant of proliferation impairment. Results show that neonatal treatment with CSA restores the whole triad of defects of the trisomic brain. In DS CSA treatment may pose caveats because it is an immunosuppressant that may cause adverse effects. However, CSA analogues that mimic its effect without eliciting immunosuppression may represent practicable tools for ameliorating brain development in individuals with DS.


Assuntos
Encéfalo/efeitos dos fármacos , Ciclosporina/farmacologia , Síndrome de Down , Neurogênese/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Animais Recém-Nascidos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Camundongos , Células-Tronco Neurais/efeitos dos fármacos
6.
Neurobiol Dis ; 106: 89-100, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28651891

RESUMO

Down syndrome (DS), a genetic condition due to triplication of Chromosome 21, is characterized by numerous neurodevelopmental alterations and intellectual disability. Individuals with DS and DS mouse models are impaired in several memory domains, including hippocampus-dependent declarative (spatial, in rodents) memory and visual recognition memory, a form of memory in which the perirhinal cortex (PRC) plays a fundamental role. The anatomo-functional substrates of hippocampus-dependent memory impairment have been largely elucidated in the Ts65Dn mouse model of DS. In contrast, there is a lack of corresponding information regarding visual recognition memory. Therefore, we deemed it of interest to examine at both an anatomical and functional level the PRC of Ts65Dn mice. We found that the PRC of adult (1.5-3.5month-old) Ts65Dn mice exhibited diffused hypocellularity and neurons with a reduced spine density. No difference between Ts65Dn and euploid mice was detected in the abundance of glutamatergic and GABAergic terminals. We examined brain slices for long-term potentiation (LTP), a form of synaptic plasticity involved in long-term memory. Theta burst stimulation of intracortical fibers was used in order to elicit LTP in the superficial layers of the PRC. We found that in trisomic slices LTP had a similar time-course but a reduced magnitude in comparison with euploid slices. While exposure to the GABAA receptor antagonist picrotoxin had no effect on LTP magnitude, exposure to the GABAB receptor antagonist CGP55845 caused an increase in LTP magnitude that became even larger than in euploid slices. Western blot analysis showed increased levels of the G-protein-activated inwardly rectifying K+ channel 2 (GIRK2) in the PRC of Ts65Dn mice, consistent with triplication of the gene coding for GIRK2. This suggests that the reduced magnitude of LTP may be caused by GIRK2-dependent exaggerated GABAB receptor-mediated inhibition. Results provide novel evidence for anatomo-functional alterations in the PRC of Ts65Dn mice. These alterations may underlie trisomy-due impairment in visual recognition memory.


Assuntos
Síndrome de Down/patologia , Síndrome de Down/fisiopatologia , Plasticidade Neuronal/fisiologia , Córtex Perirrinal/anatomia & histologia , Córtex Perirrinal/fisiopatologia , Animais , Espinhas Dendríticas/patologia , Espinhas Dendríticas/fisiologia , Modelos Animais de Doenças , Feminino , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Masculino , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Inibição Neural/fisiologia , Receptores de GABA-A/metabolismo , Receptores de GABA-B/metabolismo , Técnicas de Cultura de Tecidos , Proteínas Vesiculares de Transporte de Glutamato/metabolismo , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/metabolismo
7.
Neurobiol Dis ; 103: 11-23, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28359846

RESUMO

Neurogenesis impairment is considered a major determinant of the intellectual disability that characterizes Down syndrome (DS), a genetic condition caused by triplication of chromosome 21. Previous evidence obtained in the Ts65Dn mouse model of DS showed that the triplicated gene APP (amyloid precursor protein) is critically involved in neurogenesis alterations. In particular, excessive levels of AICD (amyloid precursor protein intracellular domain) resulting from APP cleavage by gamma-secretase increase the transcription of Ptch1, a Sonic Hedgehog (Shh) receptor that keeps the mitogenic Shh pathway repressed. Previous evidence showed that neonatal treatment with ELND006, an inhibitor of gamma-secretase, reinstates the Shh pathway and fully restores neurogenesis in Ts65Dn pups. In the framework of potential therapies for DS, it is extremely important to establish whether the positive effects of early intervention are retained after treatment cessation. Therefore, the goal of the current study was to establish whether early treatment with ELND006 leaves an enduring trace in the brain of Ts65Dn mice. Ts65Dn and euploid pups were treated with ELND006 in the postnatal period P3-P15 and the outcome of treatment was examined at ~one month after treatment cessation. We found that in treated Ts65Dn mice the pool of proliferating cells in the hippocampal dentate gyrus (DG) and total number of granule neurons were still restored as was the number of pre- and postsynaptic terminals in the stratum lucidum of CA3, the site of termination of the mossy fibers from the DG. Accordingly, patch-clamp recording from field CA3 showed functional normalization of the input to CA3. Unlike in field CA3, the number of pre- and postsynaptic terminals in the DG of treated Ts65Dn mice was no longer fully restored. The finding that many of the positive effects of neonatal treatment were retained after treatment cessation provides proof of principle demonstration of the efficacy of early inhibition of gamma-secretase for the improvement of brain development in DS.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Modelos Animais de Doenças , Síndrome de Down/tratamento farmacológico , Síndrome de Down/enzimologia , Hipocampo/enzimologia , Pirazóis/uso terapêutico , Quinolinas/uso terapêutico , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Animais Recém-Nascidos , Síndrome de Down/patologia , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/crescimento & desenvolvimento , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pirazóis/farmacologia , Quinolinas/farmacologia , Fatores de Tempo , Resultado do Tratamento
8.
Neurobiol Dis ; 82: 385-396, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26254735

RESUMO

Neurogenesis impairment starting from early developmental stages is a key determinant of intellectual disability in Down syndrome (DS). Previous evidence provided a causal relationship between neurogenesis impairment and malfunctioning of the mitogenic Sonic Hedgehog (Shh) pathway. In particular, excessive levels of AICD (amyloid precursor protein intracellular domain), a cleavage product of the trisomic gene APP (amyloid precursor protein) up-regulate transcription of Ptch1 (Patched1), the Shh receptor that keeps the pathway repressed. Since AICD results from APP cleavage by γ-secretase, the goal of the current study was to establish whether treatment with a γ-secretase inhibitor normalizes AICD levels and restores neurogenesis in trisomic neural precursor cells. We found that treatment with a selective γ-secretase inhibitor (ELND006; ELN) restores proliferation in neurospheres derived from the subventricular zone (SVZ) of the Ts65Dn mouse model of DS. This effect was accompanied by reduction of AICD and Ptch1 levels and was prevented by inhibition of the Shh pathway with cyclopamine. Treatment of Ts65Dn mice with ELN in the postnatal period P3-P15 restored neurogenesis in the SVZ and hippocampus, hippocampal granule cell number and synapse development, indicating a positive impact of treatment on brain development. In addition, in the hippocampus of treated Ts65Dn mice there was a reduction in the expression levels of various genes that are transcriptionally regulated by AICD, including APP, its origin substrate. Inhibitors of γ-secretase are currently envisaged as tools for the cure of Alzheimer's disease because they lower ßamyloid levels. Current results provide novel evidence that γ-secretase inhibitors may represent a strategy for the rescue of neurogenesis defects in DS.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Síndrome de Down/tratamento farmacológico , Proteínas Hedgehog/metabolismo , Neurogênese/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Pirazóis/farmacologia , Quinolinas/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Síndrome de Down/patologia , Síndrome de Down/fisiopatologia , Inibidores Enzimáticos/farmacologia , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/fisiopatologia , Masculino , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurogênese/fisiologia , Receptores Patched , Receptor Patched-1 , Receptores de Superfície Celular/metabolismo , Transdução de Sinais/efeitos dos fármacos , Nicho de Células-Tronco/efeitos dos fármacos , Nicho de Células-Tronco/fisiologia , Sinapses/efeitos dos fármacos , Sinapses/patologia , Sinapses/fisiologia
9.
Dev Neurobiol ; 84(4): 264-273, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39344402

RESUMO

Down syndrome (DS) is a genetic pathology characterized by various developmental defects. Unlike other clinical problems, intellectual disability is an invariant clinical trait of DS. Impairment of neurogenesis accompanied by brain hypotrophy is a typical neurodevelopmental phenotype of DS, suggesting that a reduction in the number of cells forming the brain may be a key determinant of intellectual disability. Previous evidence showed that fetuses with DS exhibit widespread hypocellularity in brain regions belonging to the temporal lobe memory systems, which may account for the typical explicit memory impairment that characterizes DS. In the current study, we have examined the basal ganglia, the insular cortex (INS), and the cingulate cortex (CCX) of fetuses with DS and age-matched controls (18-22 weeks of gestation), to establish whether cellularity defects involve regions that are not primarily involved in explicit memory. We found that fetuses with DS exhibit a notable hypocellularity in the putamen (-30%) and globus pallidus (-35%). In contrast, no cellularity differences were found in the INS and CCX, indicating that hypocellularity is not ubiquitous in the DS brain. The hypocellularity found in the basal ganglia, which are critically implicated in the control of movement, suggests that such alterations may contribute to the motor abnormalities of DS. The normal cytoarchitecture of the INS and CCX suggests that the alterations exhibited by people with DS in functions in which these regions are involved are not attributable to neuron paucity.


Assuntos
Encéfalo , Síndrome de Down , Feto , Síndrome de Down/patologia , Humanos , Encéfalo/patologia , Feminino , Masculino , Gânglios da Base/patologia , Gravidez
10.
Neuropharmacology ; 261: 110170, 2024 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-39341334

RESUMO

Intellectual disability (ID) is the unavoidable hallmark of Down syndrome (DS), a genetic condition due to triplication of chromosome 21. ID in DS is largely attributable to neurogenesis and dendritogenesis alterations taking place in the prenatal/neonatal period, the most critical time window for brain development. There are currently no treatments for ID in DS. Considering the timeline of brain development, treatment aimed at improving the neurological phenotypes of DS should be initiated as early as possible and use safe agents. The goal of this study was to establish whether it is possible to improve DS-linked neurodevelopmental defects through early treatment with polydatin, a natural polyphenol. We used the Ts65Dn mouse model of DS and focused on the hippocampus, a brain region fundamental for long-term memory. We found that in Ts65Dn mice of both sexes treated with polydatin from postnatal (P) day 3 to P15 there was full restoration of neurogenesis, neuron number, and dendritic development. These effects were accompanied by normalization of Cyclin D1 and DSCAM levels, which may account for the rescue of neurogenesis and dendritogenesis, respectively. Importantly, in Ts65Dn mice treated with polydatin from P3 to adolescence (∼P50) there was full restoration of hippocampus-dependent memory, indicating a pro-cognitive outcome of treatment. No adverse effects were observed on the body and brain weight. The efficacy and safety of polydatin in a model of DS prospect the possibility of its use during early life stages for amelioration of DS-linked neurodevelopmental alterations.


Assuntos
Modelos Animais de Doenças , Síndrome de Down , Glucosídeos , Hipocampo , Neurogênese , Estilbenos , Animais , Síndrome de Down/tratamento farmacológico , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Estilbenos/farmacologia , Estilbenos/uso terapêutico , Neurogênese/efeitos dos fármacos , Masculino , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Nootrópicos/farmacologia , Cognição/efeitos dos fármacos , Transtornos do Neurodesenvolvimento/tratamento farmacológico , Camundongos Transgênicos
11.
Sci Rep ; 11(1): 6300, 2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33737521

RESUMO

Neurogenesis impairment is a key determinant of intellectual disability in Down syndrome (DS), a genetic pathology due to triplication of chromosome 21. Since neurogenesis ceases after birth, apart in the hippocampus and olfactory bulb, the only means to tackle the problem of neurogenesis impairment in DS at its root is to intervene during gestation. A few studies in DS mouse models show that this is possible, although the drugs used may raise caveats in terms of safety. We previously found that neonatal treatment with 7,8-dihydroxyflavone (7,8-DHF), a flavonoid present in plants, restores hippocampal neurogenesis in the Ts65Dn model of DS. The goal of the current study was to establish whether prenatal treatment with 7,8-DHF improves/restores overall brain proliferation potency. Pregnant Ts65Dn females received 7,8-DHF from embryonic day 10 until delivery. On postnatal day 2 (P2) the pups were injected with BrdU and were killed after either 2 h or 52-60 days (P52-60). Evaluation of the number of proliferating (BrdU+) cells in various forebrain neurogenic niches of P2 mice showed that in treated Ts65Dn mice proliferation potency was improved or even restored in most of the examined regions, including the hippocampus. Quantification of the surviving BrdU+ cells in the dentate gyrus of P52-60 mice showed no difference between treated and untreated Ts65Dn mice. At P52-60, however, treated Ts65Dn mice exhibited a larger number of granule cells in comparison with their untreated counterparts, although their number did not reach that of euploid mice. Results show that 7,8-DHF has a widespread impact on prenatal proliferation potency in Ts65Dn mice and exerts mild long-term effects. It remains to be established whether treatment extending into the neonatal period can lead to an improvement in brain development that is retained in adulthood.


Assuntos
Encéfalo/metabolismo , Proliferação de Células/efeitos dos fármacos , Síndrome de Down/tratamento farmacológico , Síndrome de Down/metabolismo , Flavonas/administração & dosagem , Neurônios/metabolismo , Cuidado Pré-Natal/métodos , Animais , Animais Recém-Nascidos , Encéfalo/efeitos dos fármacos , Encéfalo/embriologia , Encéfalo/patologia , Bromodesoxiuridina/administração & dosagem , Modelos Animais de Doenças , Síndrome de Down/embriologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitose/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Gravidez , Resultado do Tratamento
12.
Antioxidants (Basel) ; 11(1)2021 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-35052567

RESUMO

Down syndrome (DS), a major genetic cause of intellectual disability, is characterized by numerous neurodevelopmental defects. Previous in vitro studies highlighted a relationship between bioenergetic dysfunction and reduced neurogenesis in progenitor cells from the Ts65Dn mouse model of DS, suggesting a critical role of mitochondrial dysfunction in neurodevelopmental alterations in DS. Recent in vivo studies in Ts65Dn mice showed that neonatal supplementation (Days P3-P15) with the polyphenol 7,8-dihydroxyflavone (7,8-DHF) fully restored hippocampal neurogenesis. The current study was aimed to establish whether brain mitochondrial bioenergetic defects are already present in Ts65Dn pups and whether early treatment with 7,8-DHF positively impacts on mitochondrial function. In the brain and cerebellum of P3 and P15 Ts65Dn pups we found a strong impairment in the oxidative phosphorylation apparatus, resulting in a deficit in mitochondrial ATP production and ATP content. Administration of 7,8-DHF (dose: 5 mg/kg/day) during Days P3-P15 fully restored bioenergetic dysfunction in Ts65Dn mice, reduced the levels of oxygen radicals and reinstated the hippocampal levels of PGC-1α. No pharmacotherapy is available for DS. From current findings, 7,8-DHF emerges as a treatment with a good translational potential for improving mitochondrial bioenergetics and, thus, mitochondria-linked neurodevelopmental alterations in DS.

13.
Clin Neurol Neurosurg ; 194: 105870, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32480293

RESUMO

OBJECTIVES: Down syndrome (DS) is a genetic condition characterized by cognitive disability starting from infancy. Children with DS exhibit deficits in several cognitive domains, including executive function, i.e., a set of cognitive processes that heavily depend on higher-order thalamic nuclei. The goal of this study was to establish whether executive function-related thalamic nuclei of fetuses with DS exhibit neuroanatomical alterations that may contribute to the defects in higher-order control processes seen in children with DS. PATIENTS AND METHODS: In brain sections from fetuses with DS and control fetuses (gestational week 17-22), we evaluated the cellularity in the mediodorsal nucleus (MD), the centromedian nucleus (CM), and the parafascicular nucleus (PF) of the thalamus and the density of proliferating cells in the third ventricle. RESULTS: We found that all three nuclei had a notably reduced cell density. This defect was associated with a reduced density of proliferating cells in the third ventricle, suggesting that the reduced cellularity in the MD, CM, and PF of fetuses with DS was due to neurogenesis impairment. The separate evaluation of projection neurons and interneurons in the MD, CM, and PF showed that in fetuses with DS the density of projection neurons was reduced, with no changes in interneuron density. CONCLUSION: This study provides novel evidence for DS-linked cellularity alterations in the MD, CM, and PF and suggests that altered signal processing in these nuclei may be involved in the impairment in higher-order control processes observed in individuals with DS starting from infancy.


Assuntos
Síndrome de Down/patologia , Feto/patologia , Núcleos Talâmicos/patologia , Adulto , Apoptose , Contagem de Células , Proliferação de Células , Feminino , Idade Gestacional , Humanos , Interneurônios/patologia , Núcleos Intralaminares do Tálamo/patologia , Núcleo Mediodorsal do Tálamo/patologia , Neuroglia/patologia , Neurônios/patologia , Gravidez , Terceiro Ventrículo/patologia
14.
Antioxidants (Basel) ; 8(6)2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31174258

RESUMO

No therapies currently exist for intellectual disability in Down syndrome (DS). In view of its similarities with DS, including learning and memory (L&M) defects, the Ts65Dn mouse model of DS is widely used for the design of therapy. 7,8-dihydroxyflavone (7,8-DHF), a flavonoid that targets the tropomyosin-related kinase B (TrkB) receptor of brain-derived neurotrophic factor (BDNF), exerts positive effects in various brain disease models. Based on previous demonstration that administration of 7,8-DHF in the postnatal period P3-P15 restores hippocampal neurogenesis and spinogenesis, we sought to establish whether these effects translate into behavioral benefits after treatment cessation. We found that Ts65Dn mice treated with 7,8-DHF (5.0 mg/kg/day) during postnatal days P3-P15 did not show any L&M improvement at one month after treatment cessation, indicating that the effects of 7,8-DHF on the brain are ephemeral. Based on evidence that chronic treatment with 7,8-DHF in juvenile Ts65Dn mice restores L&M, we sought to establish whether a similar effect is elicited in adulthood. We found that Ts65Dn mice treated with 7,8-DHF (5.0 mg/kg/day) for about 40 days starting from 4 months of age did not show any improvement in L&M. The results suggest that timing of therapy with 7,8-DHF is a critical issue for attainment of positive effects on the brain.

15.
Brain Pathol ; 29(3): 366-379, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30325080

RESUMO

Intellectual disability in Down syndrome (DS) has been attributed to neurogenesis impairment during fetal brain development. Consistently with explicit memory alterations observed in children with DS, fetuses with DS exhibit neurogenesis impairment in the hippocampus, a key region involved in memory formation and consolidation. Recent evidence suggests that the subiculum plays a unique role in memory retrieval, a process that is also altered in DS. While much attention has been devoted to the hippocampus, there is a striking lack of information regarding the subiculum of individuals with DS and DS models. In order to fill this gap, in the current study, we examined the subiculum of fetuses with DS and of the Ts65Dn mouse model of DS. We found that in fetuses with DS (gestational week: 17-21), the subiculum had a reduced thickness, a reduced cell density, a reduced density of progenitor cells in the ventricular zone, a reduced percentage of neurons, and an increased percentage of astrocytes and of cells immunopositive for calretinin-a protein expressed by inhibitory interneurons. Similarly to fetuses with DS, the subiculum of neonate Ts65Dn mice was reduced in size, had a reduced number of neurons and a reduced number of proliferating cells. Results suggest that the developmental defects in the subiculum of fetuses with DS may underlie impairment in recall memory and possibly other functions played by the subiculum. The finding that the subiculum of the Ts65Dn mouse exhibits neuroanatomical defects resembling those seen in fetuses with DS further validates the use of this model for preclinical studies.


Assuntos
Síndrome de Down/fisiopatologia , Hipocampo/fisiopatologia , Neurogênese/fisiologia , Animais , Animais Recém-Nascidos , Encéfalo/fisiopatologia , Cognição/fisiologia , Modelos Animais de Doenças , Feminino , Feto , Hipocampo/metabolismo , Humanos , Masculino , Memória/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/fisiologia
16.
Free Radic Biol Med ; 114: 15-32, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28756311

RESUMO

Down syndrome (DS) is characterized by brain hypotrophy and intellectual disability starting from early life stages. Accumulating evidence shows that the phenotypic features of the DS brain can be traced back to the fetal period since the DS brain exhibits proliferation potency reduction starting from the critical time window of fetal neurogenesis. This defect is worsened by the fact that neural progenitor cells exhibit reduced acquisition of a neuronal phenotype and an increase in the acquisition of an astrocytic phenotype. Consequently, the DS brain has fewer neurons in comparison with the typical brain. Although apoptotic cell death may be increased in DS, this does not seem to be the major cause of brain hypocellularity. Evidence obtained in brains of individuals with DS, DS-derived induced pluripotent stem cells (iPSCs), and DS mouse models has provided some insight into the mechanisms underlying the developmental defects due to the trisomic condition. Although many triplicated genes may be involved, in the light of the studies reviewed here, DYRK1A, APP, RCAN1 and OLIG1/2 appear to be particularly important determinants of many neurodevelopmental alterations that characterize DS because their triplication affects both the proliferation and fate of neural precursor cells as well as apoptotic cell death. Based on the evidence reviewed here, pathways downstream to these genes may represent strategic targets, for the design of possible interventions.


Assuntos
Síndrome de Down/patologia , Malformações do Sistema Nervoso/patologia , Células-Tronco Neurais/patologia , Neurogênese , Animais , Síndrome de Down/metabolismo , Humanos , Malformações do Sistema Nervoso/metabolismo , Células-Tronco Neurais/metabolismo
17.
Brain Pathol ; 28(6): 986-998, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29509279

RESUMO

Down syndrome (DS) is a genetic condition associated with impairment in several cognitive domains. Previous evidence showed a notable neurogenesis reduction in the hippocampal region of DS fetuses, which may account for the impairment of declarative memory that characterizes DS starting from early life stages. The fusiform gyrus (FG) and the inferior temporal gyrus (ITG) play a key role in visual recognition memory, a function that is impaired in children and adults with DS. The goal of the current study was to establish whether fetuses with DS (17-21 weeks of gestation) exhibit neuroanatomical alterations in the FG and ITG that may underlie recognition memory impairment. We found that the FG and ITG of fetuses with DS had a reduced thickness and fewer cells in comparison with euploid fetuses. Moreover, DS fetuses had fewer cells expressing the neuronal marker NeuN than euploid fetuses, but a similar number of cells expressing the astrocytic marker GFAP and, consequently, a higher percentage of astrocytes. Immunohistochemistry for calretinin (CR), a marker of GABAergic interneurons, showed that in DS fetuses the ratio of CR-positive vs. CR-negative cells was greater than in euploid fetuses, both in the FG (177%) and ITG (161%). An increased ratio of CR-positive vs. CR-negative cells was also found in the entorhinal cortex, hippocampus and dentate gyrus. Results provide novel evidence that the FG and ITG of DS fetuses exhibit numerous developmental defects. These defects may underlie the functional alterations in visual recognition memory observed in children with DS.


Assuntos
Síndrome de Down/embriologia , Síndrome de Down/patologia , Feto/anormalidades , Lobo Temporal/anormalidades , Astrócitos/patologia , Calbindina 2/metabolismo , Contagem de Células , Córtex Cerebral/patologia , Feminino , Desenvolvimento Fetal , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/patologia , Hipocampo/anormalidades , Humanos , Interneurônios/metabolismo , Interneurônios/patologia , Masculino , Neurogênese/fisiologia , Reconhecimento Psicológico
18.
Brain Res Bull ; 140: 378-391, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29935232

RESUMO

Individuals with Down syndrome (DS), a genetic condition due to triplication of Chromosome 21, are characterized by intellectual disability that worsens with age. Since impairment of neurogenesis and dendritic maturation are very likely key determinants of intellectual disability in DS, interventions targeted to these defects may translate into a behavioral benefit. While most of the neurogenesis enhancers tested so far in DS mouse models may pose some caveats due to possible side effects, substances naturally present in the human diet may be regarded as therapeutic tools with a high translational impact. Linoleic acid and oleic acid are major constituents of corn oil that positively affect neurogenesis and neuron maturation. Based on these premises, the goal of the current study was to establish whether treatment with corn oil improves hippocampal neurogenesis and hippocampus-dependent memory in the Ts65Dn model of DS. Four-month-old Ts65Dn and euploid mice were treated with saline or corn oil for 30 days. Evaluation of behavior at the end of treatment showed that Ts65Dn mice treated with corn oil underwent a large improvement in hippocampus-dependent learning and memory. Evaluation of neurogenesis and dendritogenesis showed that in treated Ts65Dn mice the number of new granule cells of the hippocampal dentate gyrus and their dendritic pattern became similar to those of euploid mice. In addition, treated Ts65Dn mice underwent an increase in body and brain weight. This study shows for the first time that fatty acids have a positive impact on the brain of the Ts65Dn mouse model of DS. These results suggest that a diet that is rich in fatty acids may exert beneficial effects on cognitive performance in individuals with DS without causing adverse effects.


Assuntos
Cognição , Óleo de Milho/administração & dosagem , Síndrome de Down/terapia , Neurogênese , Animais , Células Cultivadas , Modelos Animais de Doenças , Síndrome de Down/patologia , Síndrome de Down/fisiopatologia , Síndrome de Down/psicologia , Hipocampo/patologia , Hipocampo/fisiopatologia , Masculino , Memória , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/patologia , Neurônios/fisiologia
19.
Neurogenesis (Austin) ; 4(1): e1270383, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28203607

RESUMO

Neurodevelopmental alterations and cognitive disability are constant features of Down syndrome (DS), a genetic condition due to triplication of chromosome 21. DYRK1A is one of the triplicated genes that is thought to be strongly involved in brain alterations. Treatment of Dyrk1A transgenic mice with epigallocatechin gallate (EGCG), an inhibitor of DYRK1A, improves cognitive performance, suggesting that EGCG may represent a suitable treatment of DS. Evidence in the Ts65Dn mouse model of DS shows that EGCG restores hippocampal development, although this effect is ephemeral. Other studies, however, show no effects of treatment on hippocampus-dependent memory. On the other hand, a pilot study in young adults with DS shows that EGCG transiently improves some aspects of memory. Interestingly, EGCG plus cognitive training engenders effects that are more prolonged. Studies in various rodent models show a positive impact of EGCG on brain and behavior, but other studies show no effect. In spite of these discrepancies, possibly due to heterogeneity of protocols/timing/species, EGCG seems to exert some beneficial effects on the brain. It is possible that protocols of periodic EGCG administration to individuals with DS (alone or in conjunction with other treatments) may prevent the disappearance of its effects.

20.
CNS Neurol Disord Drug Targets ; 16(7): 812-819, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27488422

RESUMO

BACKGROUND & OBJECTIVE: Down syndrome, a genetic condition caused by triplication of chromosome 21, is characterized by widespread neurogenesis reduction and cognitive impairment. Unlike other brain functions, smell is not impaired at early life stages and olfactory deterioration begins to appear in adulthood. Similarly to individuals with Down syndrome, in the Ts65Dn mouse model of Down syndrome smell function is normal at early life stages. Smell impairment only appears in adulthood associated with a reduction in the number of new granule neurons migrated to the olfactory bulb from the subventricular zone. Based on evidence that lithium positively impacts neurogenesis, the goal of current study was to establish whether treatment with lithium restores olfactory bulb neurogenesis and olfactory performance in middle-aged Ts65Dn mice. METHOD: Euploid and Ts65Dn mice aged 13 months were treated with lithium chow or control chow for one month. Before the end of treatment, mice were injected with BrdU, in order to label proliferating cells. Results showed that in Ts65Dn mice lithium treatment restored the number of neural precursor cells in the subventricular zone of the lateral ventricle, rostral migratory stream and olfactory bulb. This effect was accompanied by restoration of olfactory performance. Unlike in olfactory neurogenic regions, treatment had no neurogenesis-enhancing effect on the subgranular zone of the hippocampal dentate gyrus, indicating that lithium has no generalized positive effect on the brain. CONCLUSION: Results suggest that lithium may have a positive impact in brain disorders that, similarly to Down syndrome, are characterized by olfactory decline and neurogenesis impairment in the subventricular zone.


Assuntos
Síndrome de Down/tratamento farmacológico , Lítio/uso terapêutico , Neurogênese/efeitos dos fármacos , Transtornos do Olfato/tratamento farmacológico , Olfato/efeitos dos fármacos , Fatores Etários , Animais , Proliferação de Células/efeitos dos fármacos , Giro Denteado/efeitos dos fármacos , Giro Denteado/fisiologia , Modelos Animais de Doenças , Síndrome de Down/complicações , Síndrome de Down/genética , Síndrome de Down/fisiopatologia , Feminino , Ventrículos Laterais/efeitos dos fármacos , Ventrículos Laterais/fisiologia , Lítio/farmacologia , Camundongos , Mutação , Transtornos do Olfato/complicações , Transtornos do Olfato/patologia , Transtornos do Olfato/fisiopatologia , Bulbo Olfatório/efeitos dos fármacos , Bulbo Olfatório/fisiologia , Olfato/fisiologia
SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa