A influência genética sobre a memória humana: uma revisão

The acquisition, storage and recall of information are important process to memory formation. Age-associated memory impairment was described by the first time in 1986 by National Institute of Mental Health, and potentials risk factors have been investigated, both environmental and genetics. Once the number of studies about the genetic influence on memory impairment is increasing in the last years, the objective of this work is to review the available results about the subject. A systematic review was done, including papers that investigated the association among genetic variants and memory scores. It was included results of all papers found in the PubMed database since 2000. The literature show that genes related to lipid transport in the nervous system (APOE e APOC1), to serotonin (HTR2A e 5-HTTLRP), to dopamine (DRD1, DRD3, DRD4, COMT e DAT) and to other neurobiology related functions (BDNF e ECA) were associated to some memory injury. Once the genetic profile is determined to the population, it is very important to verify the interaction among studied genes, besides between these genes and different environmental factors on memory impairment susceptibility. These kind of data will make possible personalized intervention strategies to each situation, mitigating the effect of these variables on mental health.A aquisição, armazenamento e evocação de informações são processos importantes para a formação da memória. O déficit de memória associado ao envelhecimento foi descrito em 1986 pelo National Institute of Mental Health, e potenciais fatores de risco têm sido investigados, tanto ambientais como genéticos. Assim, o número de trabalhos investigando a influência genética sobre déficit de memória vem crescendo nos últimos anos, com publicações indicando a influência de uma série de genes. Portanto, foi realizada uma revisão sistemática de artigos que investigaram a associação de variantes genéticas e escores de memória. Foram incluídos resultados de todos os artigos encontrados na base de dados Pubmed desde o ano de 2000. A literatura demonstra que genes relacionados ao transporte de lipídios no sistema nervoso (APOE e APOC1), à serotonina (HTR2A e 5-HTTLRP), à dopamina (DRD1, DRD3, DRD4, COMT e DAT) e a outras funções relacionadas à neurobiologia (BDNF e ECA) foram associados a algum prejuízo na memória. Uma vez determinado o perfil genético da população, é de grande importância verificar a interação entre os genes estudados, bem como entre estes genes e fatores ambientais diversos na suscetibilidade ao déficit de memória, possibilitando estratégias de intervenção personalizadas para cada situação, atenuando os efeitos destas variáveis sobre a saúde mental.

Antiapoptotic effects of cannabidiol in an experimental model of cognitive decline induced by brain iron overload

Iron accumulation in the brain has been recognized as a common feature of both normal aging and neurodegenerative diseases. Cognitive dysfunction has been associated to iron excess in brain regions in humans. We have previously described that iron overload leads to severe memory deficits, including spatial, recognition, and emotional memory impairments in adult rats. In the present study we investigated the effects of neonatal iron overload on proteins involved in apoptotic pathways, such as Caspase 8, Caspase 9, Caspase 3, Cytochrome c, APAF1, and PARP in the hippocampus of adult rats, in an attempt to establish a causative role of iron excess on cell death in the nervous system, leading to memory dysfunction. Cannabidiol (CBD), the main non-psychotropic component of Cannabis sativa, was examined as a potential drug to reverse iron-induced effects on the parameters analyzed. Male rats received vehicle or iron carbonyl (30 mg/kg) from the 12th to the 14th postnatal days and were treated with vehicle or CBD (10 mg/kg) for 14 days in adulthood. Iron increased Caspase 9, Cytochrome c, APAF1, Caspase 3 and cleaved PARP, without affecting cleaved Caspase 8 levels. CBD reversed iron-induced effects, recovering apoptotic proteins Caspase 9, APAF1, Caspase 3 and cleaved PARP to the levels found in controls. These results suggest that iron can trigger cell death pathways by inducing intrinsic apoptotic proteins. The reversal of iron-induced effects by CBD indicates that it has neuroprotective potential through its anti-apoptotic action

Altera??es nas prote?nas de fiss?o e fus?o mitocondriais, caspase 3 e sinaptofisina cerebrais induzidas pela sobrecarga de ferro neonatal : revers?o pelo tratamento com canabidiol

Made available in DSpace on 2015-04-14T14:51:24Z (GMT). No. of bitstreams: 1 448467.pdf: 1354318 bytes, checksum: e98c36f8757b493a6c1604f1618bfb2d (MD5) Previous issue date: 2013-02-08Iron accumulation in the brain has been observed in both normal aging and in several neurodegenerative diseases. We have previously shown that brain iron loading results in persistent memory deficits, which are accompanied by oxidative stress. Due to the high metabolic rate of the nervous system, mitochondria are present in large numbers in nerve cells. It has been demonstrated that through fission and fusion of mitochondria, these organelles promote changes in their structure and this dynamic can affect mitochondrial function and vice-versa. Deficits in supplying energy to the synapses have been linked to neurodegenerative diseases and once the functionality of neural circuits is reduced, these cells may activate neuronal death cascades. Here, we analyzed the effects of neonatally iron treatment on the following targets: Dynamin-1-like protein (DNM1L) and Optic atrophy 1 (OPA1), proteins involved in regulating mitochondrial fission and fusion, respectively; Caspase 3, a key protease of the effector phase of apoptosis; and Synaptophysin, as a synaptic marker. Additionally, we investigated the effects of Cannabidiol (CBD), the main non-psychotropic component of Cannabis sativa, previously shown to improve memory in iron-treated rats, in reversing iron-induced effects on DNM1L, OPA1, caspase 3, and synaptophysin. Male rats received vehicle or iron carbonyl (30mg/kg) at postnatal days 12-14. At adulthood, they were treated with vehicle or CBD (10 mg/kg) for 14 days. Hippocampal and cortical protein levels and gene expression were quantified using western blotting analysis and RT-qPCR, respectively. Quantitative measurements of proteins were made using densities of individual proteins, normalized to the density of β-actin. On RT-qPCR, samples were normalized to three reference genes (GAPDH, HPRT1 and RPL13A). Western blotting results indicated that neonatal iron treatment induced a significant reduction of DNM1L in the hippocampus and OPA1 in the cortex. Iron was also shown to increase caspase 3 both in the hippocampus and cortex, which was accompanied by a significant reduction of synaptophysin levels in the hippocampus. CBD reversed iron-induced effects, bringing hippocampal DNM1L, caspase 3 and synaptophysin levels back to values comparable to the control group. The present results suggest that iron may affect mitochondrial dynamics, possibly trigging synaptic loss and apoptotic cell death. The reversion of these effects by CBD, indicates its potential neuroprotective effect.O ac?mulo de ferro no c?rebro tem sido observado tanto no envelhecimento normal quanto em muitas doen?as neurodegenerativas. Previamente, mostramos que a sobrecarga de ferro no c?rebro resulta em d?ficits de mem?ria persistentes, acompanhados por estresse oxidativo. Devido ? elevada taxa metab?lica do sistema nervoso, as mitoc?ndrias est?o presentes em grande n?mero em c?lulas nervosas. Tem sido demonstrado que, por meio da fiss?o e fus?o, essas organelas promovem altera??es na sua estrutura e essa din?mica pode afetar a fun??o mitocondrial e vice-versa. D?ficits no fornecimento de energia para as sinapses t?m sido associados a doen?as neurodegenerativas e com a redu??o da funcionalidade de circuitos neurais essas c?lulas podem ativar cascatas de morte neuronal. No presente trabalho, foram analisados os efeitos do tratamento do ferro neonatal sobre os seguintes alvos: prote?na 1 semelhante ? dinamina (DNM1L) e prote?na atr?fica ?ptica 1 (OPA1), envolvidas na regula??o de fiss?o e de fus?o mitocondrial, respectivamente; caspase 3, uma protease essencial da fase efetora da apoptose; e sinaptofisina, um marcador sin?ptico. Al?m disso, n?s investigamos os efeitos do canabidiol (CBD), principal componente n?o psicotr?pico da Cannabis sativa, j? mostrado capaz de melhorar a mem?ria de ratos tratados com ferro, na revers?o dos efeitos induzidos pelo ferro sobre as prote?nas DNM1L, OPA1, caspase 3 e sinaptofisina. Ratos machos receberam ve?culo ou ferro carbonila (30mg/kg) do 12? ao 14? dia p?s-natal. Na idade adulta, foram tratados com ve?culo ou CBD (10mg/kg) durante 14 dias. Os n?veis proteicos e a express?o g?nica no hipocampo e c?rtex foram quantificados atrav?s de Western blotting e RT-qPCR, respectivamente. A quantifica??o das prote?nas foi realizada atrav?s da medida das densidades das bandas individuais, normalizadas pela densidade de β-actina. Para o RT-qPCR, as amostras foram normalizadas para 3 genes de refer?ncia (GAPDH, HPRT1 e RPL13A). Os resultados da an?lise prot?ica indicaram que o tratamento com ferro no per?odo neonatal induziu redu??o de DNM1L no hipocampo e OPA1 no c?rtex. O ferro tamb?m aumentou os n?veis de caspase 3 tanto no hipocampo quanto no c?rtex, acompanhado por redu??o dos n?veis de sinaptofisina no hipocampo. O CBD reverteu os efeitos induzidos pelo ferro, trazendo os n?veis hipocampais de DNM1L, caspase 3 e sinaptofisina de volta aos valores compar?veis ao grupo controle. Os resultados sugerem que o ferro pode afetar a din?mica mitocondrial, possivelmente desencadeando perda sin?ptica e morte celular por apoptose. A revers?o desses efeitos pelo CBD indica o seu potencial efeito neuroprotetor

Efeitos do Canabidiol sobre par?metros mitocondriais e apopt?ticos em hipocampo de ratos tratados com ferro no per?odo neonatal

Submitted by PPG Biologia Celular e Molecular ([email protected]) on 2018-04-06T17:32:47Z No. of bitstreams: 1 VANESSA_KAPPEL_DASILVA_TES.pdf: 5900313 bytes, checksum: 98206f797d5710ed04b0cd1d6529092e (MD5)Approved for entry into archive by Caroline Xavier ([email protected]) on 2018-04-16T19:58:40Z (GMT) No. of bitstreams: 1 VANESSA_KAPPEL_DASILVA_TES.pdf: 5900313 bytes, checksum: 98206f797d5710ed04b0cd1d6529092e (MD5)Made available in DSpace on 2018-04-16T20:04:27Z (GMT). No. of bitstreams: 1 VANESSA_KAPPEL_DASILVA_TES.pdf: 5900313 bytes, checksum: 98206f797d5710ed04b0cd1d6529092e (MD5) Previous issue date: 2018-03-07Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPESBrain iron accumulation has been observed both in normal aging and in many neurodegenerative diseases. In previous studies, we have described that brain iron overload results in persistent memory deficits, accompanied by oxidative stress. The high metabolic rate of the nervous system makes mitochondria essential for nerve cells. These organelles control iron homeostasis in its interior and the management of reactive oxygen species. When deregulation in these activities occurs, mitochondrial functioning is compromised, resulting in failures in the energy supply mainly for the synapses. Inadequate functioning of neural circuits may culminate in the activation of cell death pathways, a feature strongly associated with neurodegenerative diseases. In the present study we analyzed the effects of neonatal iron overload on complex I deletions in the mitochondrial DNA ; on methylation and hydroxymethylation of mitochondrial DNA; on mitochondrial proteins involved on iron homeostasis, on the enzymatic activity of Succinate Dehydrogenase and Creatine Kinase, enzymes involved in the cells energy supply; and on proteins involved in apoptotic pathways, such as Caspase 8, Caspase 9, Caspase 3, Cytochrome c, APAF1, and PARP in the hippocampus of adult rats. In addition, we investigated the effects of cannabidiol (CBD), the main non-psychotropic component of Cannabis sativa, in reversing iron-induced effects on all parameters analyzed. Male rats received vehicle or iron carbonyl (30 mg / kg) from the 12th to the 14th postnatal day and were treated with vehicle or CBD (10mg / kg) for 14 days in adulthood. Iron treatment induced increased deletions of mitochondrial DNA and expression of proteins involved in apoptosis, while induced reductions of methylation and hydroxymethylation, enzymatic activity and mitochondrial ferritin, an iron storage protein. CBD reversed iron-induced effects, recovering hydroxymethylation levels, mitochondrial ferritin, Succinate dehydrogenase activity, apoptotic proteins Caspase 3, Caspase 9, PARP and APAF1 at levels comparable to controls. These results suggest that iron can affect mechanisms of mitochondrial functioning and trigger cell death pathways by apoptosis. The reversal of some of these effects by CBD indicates its neuroprotective potential.O ac?mulo de ferro no c?rebro tem sido observado tanto no envelhecimento normal quanto em muitas doen?as neurodegenerativas. Nossos estudos anteriores mostraram que a sobrecarga de ferro cerebral resulta em d?ficits de mem?ria persistentes, acompanhados por estresse oxidativo. A elevada taxa metab?lica do sistema nervoso torna as mitoc?ndrias essenciais para c?lulas nervosas. Essas organelas t?m como fun??o o controle da homeostasia do ferro em seu interior e o gerenciamento das esp?cies reativas de oxig?nio. Uma vez que ocorre desregula??o nessas atividades, o funcionamento das mitoc?ndrias fica comprometido, resultando em falhas no aporte energ?tico principalmente para as sinapses. O funcionamento inadequado de circuitos neurais pode culminar na ativa??o de vias de morte celular, uma caracter?stica bastante associada ?s doen?as neurodegenerativas. No presente trabalho analisamos os efeitos da sobrecarga de ferro neonatal sobre as dele??es no complexo I do DNA mitocondrial; sobre os mecanismos de metila??o e hidroximetila??o do DNA mitocondrial; sobre prote?nas envolvidas no metabolismo de ferro mitocondrial (Ferritina mitocondrial e Mitoferrina 2), sobre a atividade enzim?tica da Succinato desidrogenase e Creatina quinase, envolvidas no aporte energ?tico para as c?lulas; e sobre prote?nas envolvidas nas vias apopt?ticas, como a Caspase 8, Caspase 9, Caspase 3, Citocromo c, APAF1 e PARP em hipocampos de ratos adultos. Al?m disso, investigamos os efeitos do canabidiol (CBD), principal componente n?o psicotr?pico da Cannabis sativa, na revers?o dos efeitos induzidos pelo ferro sobre todos os par?metros analisados. Ratos machos receberam ve?culo ou ferro carbonila (30 mg/kg) do 12? ao 14? dia p?s-natal e na idade adulta foram tratados com ve?culo ou CBD (10 mg/kg) durante 14 dias. O tratamento com ferro induziu o aumento das dele??es do DNA mitocondrial e das prote?nas envolvidas na via intr?nseca da apoptose, enquanto induziu a redu??o de metila??o e hidroximetila??o no DNA mitocondrial, bem como da atividade enzim?tica e da ferritina mitocondrial, prote?na de armazenamento de ferro. O CBD reverteu os efeitos induzidos pelo ferro, recuperando os n?veis de hidroximetila??o, de ferritina mitocondrial, da atividade da Succinato dehidrogenase, e das prote?nas apopt?ticas Caspase 3, Caspase 9, PARP e APAF1 a n?veis compar?veis com o controle. Os resultados sugerem que o ferro pode afetar mecanismos de funcionamento mitocondrial e desencadear vias de morte celular por apoptose. A revers?o de alguns desses efeitos pelo CBD indica o seu potencial neuroprotetor

A influência genética sobre a memória humana: uma revisão

The acquisition, storage and recall of information are important process to memory formation. Age-associated memory impairment was described by the first time in 1986 by National Institute of Mental Health, and potentials risk factors have been investigated, both environmental and genetics. Once the number of studies about the genetic influence on memory impairment is increasing in the last years, the objective of this work is to review the available results about the subject. A systematic review was done, including papers that investigated the association among genetic variants and memory scores. It was included results of all papers found in the PubMed database since 2000. The literature show that genes related to lipid transport in the nervous system (APOE e APOC1), to serotonin (HTR2A e 5-HTTLRP), to dopamine (DRD1, DRD3, DRD4, COMT e DAT) and to other neurobiology related functions (BDNF e ECA) were associated to some memory injury. Once the genetic profile is determined to the population, it is very important to verify the interaction among studied genes, besides between these genes and different environmental factors on memory impairment susceptibility. These kind of data will make possible personalized intervention strategies to each situation, mitigating the effect of these variables on mental health.A aquisição, armazenamento e evocação de informações são processos importantes para a formação da memória. O déficit de memória associado ao envelhecimento foi descrito em 1986 pelo National Institute of Mental Health, e potenciais fatores de risco têm sido investigados, tanto ambientais como genéticos. Assim, o número de trabalhos investigando a influência genética sobre déficit de memória vem crescendo nos últimos anos, com publicações indicando a influência de uma série de genes. Portanto, foi realizada uma revisão sistemática de artigos que investigaram a associação de variantes genéticas e escores de memória. Foram incluídos resultados de todos os artigos encontrados na base de dados Pubmed desde o ano de 2000. A literatura demonstra que genes relacionados ao transporte de lipídios no sistema nervoso (APOE e APOC1), à serotonina (HTR2A e 5-HTTLRP), à dopamina (DRD1, DRD3, DRD4, COMT e DAT) e a outras funções relacionadas à neurobiologia (BDNF e ECA) foram associados a algum prejuízo na memória. Uma vez determinado o perfil genético da população, é de grande importância verificar a interação entre os genes estudados, bem como entre estes genes e fatores ambientais diversos na suscetibilidade ao déficit de memória, possibilitando estratégias de intervenção personalizadas para cada situação, atenuando os efeitos destas variáveis sobre a saúde mental.

INVESTIGAÇÃO DA INFLUÊNCIA DO GENE APOE SOBRE ESCORES DE MEMÓRIA EM IDOSOS

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INVESTIGAÇÃO DA INFLUÊNCIA DO GENE APOE SOBRE ESCORES DE MEMÓRIA EM IDOSOS

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