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1.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805772

RESUMO

Sulforaphane, a potent dietary bioactive agent obtainable from cruciferous vegetables, has been extensively studied for its effects in disease prevention and therapy. Sulforaphane potently induces transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated expression of detoxification, anti-oxidation, and immune system-modulating enzymes, and possibly acts as an anti-carcinogenic agent. Several clinical trials are in progress to study the effect of diverse types of cruciferous vegetables and sulforaphane on prostate cancer, breast cancer, lung cancer, atopic asthmatics, skin aging, dermatitis, obesity, etc. Recently, the protective effects of sulforaphane on brain health were also considerably studied, where the studies have further extended to several neurological diseases, including Alzheimer's disease (AD), Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, autism spectrum disorder, and schizophrenia. Animal and cell studies that employ sulforaphane against memory impairment and AD-related pre-clinical biomarkers on amyloid-ß, tau, inflammation, oxidative stress, and neurodegeneration are summarized, and plausible neuroprotective mechanisms of sulforaphane to help prevent AD are discussed. The increase in pre-clinical evidences consistently suggests that sulforaphane has a multi-faceted neuroprotective effect on AD pathophysiology. The anti-AD-like evidence of sulforaphane seen in cells and animals indicates the need to pursue sulforaphane research for relevant biomarkers in AD pre-symptomatic populations.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/genética , Isotiocianatos/farmacologia , Transtornos da Memória/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Sulfóxidos/farmacologia , Proteínas tau/genética , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Biomarcadores/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Esquema de Medicação , Avaliação Pré-Clínica de Medicamentos , Regulação da Expressão Gênica , Humanos , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Agregados Proteicos/efeitos dos fármacos , Agregados Proteicos/genética , Proteínas tau/antagonistas & inibidores , Proteínas tau/metabolismo
2.
Nat Commun ; 12(1): 1903, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33771994

RESUMO

Aberrant regulation of microRNAs (miRNAs) has been implicated in the pathogenesis of Alzheimer's disease (AD), but most abnormally expressed miRNAs found in AD are not regulated by synaptic activity. Here we report that dysfunction of miR-135a-5p/Rock2/Add1 results in memory/synaptic disorder in a mouse model of AD. miR-135a-5p levels are significantly reduced in excitatory hippocampal neurons of AD model mice. This decrease is tau dependent and mediated by Foxd3. Inhibition of miR-135a-5p leads to synaptic disorder and memory impairments. Furthermore, excess Rock2 levels caused by loss of miR-135a-5p plays an important role in the synaptic disorder of AD via phosphorylation of Ser726 on adducin 1 (Add1). Blocking the phosphorylation of Ser726 on Add1 with a membrane-permeable peptide effectively rescues the memory impairments in AD mice. Taken together, these findings demonstrate that synaptic-related miR-135a-5p mediates synaptic/memory deficits in AD via the Rock2/Add1 signaling pathway, illuminating a potential therapeutic strategy for AD.


Assuntos
Doença de Alzheimer/genética , Proteínas do Citoesqueleto/genética , Transtornos da Memória/genética , MicroRNAs/genética , Sinapses/metabolismo , Quinases Associadas a rho/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Animais , Células Cultivadas , Proteínas do Citoesqueleto/metabolismo , Modelos Animais de Doenças , Hipocampo/citologia , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neurônios/metabolismo , Neurônios/fisiologia , Fosforilação , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Sinapses/fisiologia , Quinases Associadas a rho/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismo
3.
Mol Med Rep ; 23(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33604684

RESUMO

Alzheimer's disease (AD) is the most common form of dementia that is primarily characterized by progressive cognitive deficits. The toxicity of amyloid ß­protein (Aß) serves an important role in the progression of AD, resulting in neuronal loss via a number of possible mechanisms, including oxidative stress, mitochondrial dysfunction, energy depletion, apoptosis and neuroinflammation. Previous studies have reported that cocaine amphetamine regulated transcript (CART) treatment improves memory and synaptic structure in APP/PS1 mice. Therefore, the present study aimed to investigate whether CART served a protective role against memory deficits in AD. APP/PS1 mice were treated with CART or PBS. Spatial memory was assessed using the Morris water maze. Oxidative stress and DNA damage were compared among wild­type, APP/PS1 and CART­treated APP/PS1 mice. The mRNA and protein expression levels of Aß metabolism­associated enzymes, including neprilysin (NEP), insulin­degrading enzyme (IDE), receptor for advanced glycation end products (RAGE) and low­density lipoprotein receptor­related protein 1 (LRP­1), in the hippocampus were measured via reverse transcription­quantitative PCR and western blotting, respectively. CART improved the memory impairment of APP/PS1 mice by reducing oxidative stress, inhibiting DNA damage and protecting against mitochondrial dysfunction in the cerebral cortex and hippocampus. CART also reduced cell senescence and oxidative stress in Aß1­42­exposed primary cortical neurons in APP/PS1 mice. Moreover, CART promoted Aß degradation via modulating Aß metabolism­associated enzymes, including IDE, NEP, LRP­1 and RAGE. Collectively, the present study indicated that CART improved the learning and memory capacity of APP/PS mice, thus may have potential to serve as a novel therapeutic agent for AD.


Assuntos
Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Disfunção Cognitiva/genética , Estresse Oxidativo/genética , Presenilina-1/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/genética , Peptídeos beta-Amiloides/genética , Animais , Senescência Celular/genética , Disfunção Cognitiva/patologia , Dano ao DNA/genética , Modelos Animais de Doenças , Hipocampo/enzimologia , Hipocampo/patologia , Humanos , Insulisina/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Transtornos da Memória/genética , Transtornos da Memória/patologia , Camundongos , Camundongos Transgênicos , Neprilisina/genética , Placa Amiloide/genética , Placa Amiloide/patologia , Receptor para Produtos Finais de Glicação Avançada/genética , Memória Espacial/fisiologia
4.
Environ Health Prev Med ; 26(1): 8, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33451279

RESUMO

BACKGROUND: Prenatal stress can cause neurobiological and behavioral defects in offspring; environmental factors play a crucial role in regulating the development of brain and behavioral; this study was designed to test and verify whether an enriched environment can repair learning and memory impairment in offspring rats induced by prenatal stress and to explore its mechanism involving the expression of insulin-like growth factor-2 (IGF-2) and activity-regulated cytoskeletal-associated protein (Arc) in the hippocampus of the offspring. METHODS: Rats were selected to establish a chronic unpredictable mild stress (CUMS) model during pregnancy. Offspring were weaned on 21st day and housed under either standard or an enriched environment. The learning and memory ability were tested using Morris water maze and Y-maze. The expression of IGF-2 and Arc mRNA and protein were respectively measured by using RT-PCR and Western blotting. RESULTS: There was an elevation in the plasma corticosterone level of rat model of maternal chronic stress during pregnancy. Maternal stress's offspring exposed to an enriched environment could decrease their plasma corticosterone level and improve their weight. The offspring of maternal stress during pregnancy exhibited abnormalities in Morris water maze and Y-maze, which were improved in an enriched environment. The expression of IGF-2, Arc mRNA, and protein in offspring of maternal stress during pregnancy was boosted and some relationships existed between these parameters after being exposed enriched environment. CONCLUSIONS: The learning and memory impairment in offspring of prenatal stress can be rectified by the enriched environment, the mechanism of which is related to the decreasing plasma corticosterone and increasing hippocampal IGF-2 and Arc of offspring rats following maternal chronic stress during pregnancy.


Assuntos
Proteínas do Citoesqueleto/genética , Regulação da Expressão Gênica , Fator de Crescimento Insulin-Like II/genética , Deficiências da Aprendizagem/genética , Transtornos da Memória/genética , Proteínas do Tecido Nervoso/genética , Efeitos Tardios da Exposição Pré-Natal/genética , Meio Social , Estresse Psicológico/genética , Animais , Proteínas do Citoesqueleto/metabolismo , Feminino , Hipocampo/metabolismo , Fator de Crescimento Insulin-Like II/metabolismo , Aprendizagem , Deficiências da Aprendizagem/psicologia , Masculino , Transtornos da Memória/psicologia , Proteínas do Tecido Nervoso/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/psicologia , Distribuição Aleatória , Ratos , Ratos Wistar
5.
Metabolism ; 116: 154463, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33309713

RESUMO

OBJECTIVES: GDI1 gene encodes for αGDI, a protein controlling the cycling of small GTPases, reputed to orchestrate vesicle trafficking. Mutations in human GDI1 are responsible for intellectual disability (ID). In mice with ablated Gdi1, a model of ID, impaired working and associative short-term memory was recorded. This cognitive phenotype worsens if the deletion of αGDI expression is restricted to neurons. However, whether astrocytes, key homeostasis providing neuroglial cells, supporting neurons via aerobic glycolysis, contribute to this cognitive impairment is unclear. METHODS: We carried out proteomic analysis and monitored [18F]-fluoro-2-deoxy-d-glucose uptake into brain slices of Gdi1 knockout and wild type control mice. d-Glucose utilization at single astrocyte level was measured by the Förster Resonance Energy Transfer (FRET)-based measurements of cytosolic cyclic AMP, d-glucose and L-lactate, evoked by agonists selective for noradrenaline and L-lactate receptors. To test the role of astrocyte-resident processes in disease phenotype, we generated an inducible Gdi1 knockout mouse carrying the Gdi1 deletion only in adult astrocytes and conducted behavioural tests. RESULTS: Proteomic analysis revealed significant changes in astrocyte-resident glycolytic enzymes. Imaging [18F]-fluoro-2-deoxy-d-glucose revealed an increased d-glucose uptake in Gdi1 knockout tissue versus wild type control mice, consistent with the facilitated d-glucose uptake determined by FRET measurements. In mice with Gdi1 deletion restricted to astrocytes, a selective and significant impairment in working memory was recorded, which was rescued by inhibiting glycolysis by 2-deoxy-d-glucose injection. CONCLUSIONS: These results reveal a new astrocyte-based mechanism in neurodevelopmental disorders and open a novel therapeutic opportunity of targeting aerobic glycolysis, advocating a change in clinical practice.


Assuntos
Desoxiglucose/farmacologia , Glicólise/efeitos dos fármacos , Inibidores de Dissociação do Nucleotídeo Guanina/genética , Deficiência Intelectual/genética , Transtornos da Memória/prevenção & controle , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células Cultivadas , Desoxiglucose/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Glucose/metabolismo , Inibidores de Dissociação do Nucleotídeo Guanina/deficiência , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Transtornos da Memória/genética , Camundongos , Camundongos Knockout
6.
PLoS One ; 15(12): e0244725, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33382797

RESUMO

The pathogenesis of human immunodeficiency virus associated neurological disorders is still not well understood, yet is known to result in neurological declines despite combination anti-retroviral therapy. HIV-1 transgenic (Tg26) mice contain integrated non-infectious HIV-1 proviral DNA. We sought to assess the integrity of neurocognitive function and sensory systems in HIV-1 Tg26 mice using a longitudinal design, in both sexes, to examine both age- and sex-related disease progression. General neurological reflexive testing showed only acclimation to repeated testing by all groups. Yet, at 2.5 months of age, female Tg26 +/- mice showed hyposensitivity to noxious hot temperatures, compared to wild types (both sexes) and male Tg26 +/- mice, that worsened by 10 months of age. Female Tg26 +/- mice had short-term spatial memory losses in novel object location memory testing at 2.5 and 7 months, compared to female wild types; changes not observed in male counterparts. Female Tg26 +/- mice showed mild learning deficits and short- and long-term spatial memory deficits in olfactory and visually cued Barnes Maze testing at 3 months of age, yet greater learning and memory deficits by 8 months. In contrast, male Tg26 +/- mice displayed no learning deficits and fewer spatial memory deficits (mainly heading errors in nontarget holes). Thus, greater sex-specific temperature hyposensitivity and spatial memory declines were observed in female HIV Tg26 +/- mice, than in male Tg26 +/- mice, or their wild type littermates, that increased with aging. Additionally, tibial bones were examined using ex vivo micro-CT after tissue collection at 11 months. Sex-dependent increases in bone volume and trabecular number were seen in males, matching their greater weights at this age. These results indicate that HIV-1 Tg26 mice is a promising model in which to study neuropathic mechanisms underlying peripheral pathology as well as cognitive deficits seen with HIV.


Assuntos
Temperatura Corporal/fisiologia , HIV-1/genética , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/genética , Memória Espacial/fisiologia , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Fatores Sexuais
7.
Int J Mol Sci ; 21(24)2020 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-33322202

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disease characterized by neurological dysfunction, including memory impairment, attributed to the accumulation of amyloid ß (Aß) in the brain. Although several studies reported possible mechanisms involved in Aß pathology, much remains unknown. Previous findings suggested that a protein regulated in development and DNA damage response 1 (REDD1), a stress-coping regulator, is an Aß-responsive gene involved in Aß cytotoxicity. However, we still do not know how Aß increases the level of REDD1 and whether REDD1 mediates Aß-induced synaptic dysfunction. To elucidate this, we examined the effect of Aß on REDD1-expression using acute hippocampal slices from mice, and the effect of REDD1 short hairpin RNA (shRNA) on Aß-induced synaptic dysfunction. Lastly, we observed the effect of REDD1 shRNA on memory deficit in an AD-like mouse model. Through the experiments, we found that Aß-incubated acute hippocampal slices showed increased REDD1 levels. Moreover, Aß injection into the lateral ventricle increased REDD1 levels in the hippocampus. Anisomycin, but not actinomycin D, blocked Aß-induced increase in REDD1 levels in the acute hippocampal slices, suggesting that Aß may increase REDD1 translation rather than transcription. Aß activated Fyn/ERK/S6 cascade, and inhibitors for Fyn/ERK/S6 or mGluR5 blocked Aß-induced REDD1 upregulation. REDD1 inducer, a transcriptional activator, and Aß blocked synaptic plasticity in the acute hippocampal slices. REDD1 inducer inhibited mTOR/Akt signaling. REDD1 shRNA blocked Aß-induced synaptic deficits. REDD1 shRNA also blocked Aß-induced memory deficits in passive-avoidance and object-recognition tests. Collectively, these results demonstrate that REDD1 participates in Aß pathology and could be a target for AD therapy.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/farmacologia , Hipocampo/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Transtornos da Memória/metabolismo , Sinapses/metabolismo , Fatores de Transcrição/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Anisomicina/farmacologia , Dactinomicina/farmacologia , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Masculino , Transtornos da Memória/genética , Transtornos da Memória/patologia , Testes de Memória e Aprendizagem , Camundongos , Biossíntese de Proteínas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-fyn/metabolismo , RNA Interferente Pequeno , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/genética , Sinapses/patologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/genética , Regulação para Cima
8.
Lab Invest ; 100(9): 1238-1251, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32350405

RESUMO

The mechanisms which underlie defects in learning and memory are a major area of focus with the increasing incidence of Alzheimer's disease in the aging population. The complex genetically-controlled, age-, and environmentally-dependent onset and progression of the cognitive deficits and neuronal pathology call for better understanding of the fundamental biology of the nervous system function. In this study, we focus on nuclear receptor binding factor-2 (NRBF2) which modulates the transcriptional activities of retinoic acid receptor α and retinoid X receptor α, and the autophagic activities of the BECN1-VPS34 complex. Since both transcriptional regulation and autophagic function are important in supporting neuronal function, we hypothesized that NRBF2 deficiency may lead to cognitive deficits. To test this, we developed a new mouse model with nervous system-specific knockout of Nrbf2. In a series of behavioral assessment, we demonstrate that NRBF2 knockout in the nervous system results in profound learning and memory deficits. Interestingly, we did not find deficits in autophagic flux in primary neurons and the autophagy deficits were minimal in the brain. In contrast, RNAseq analyses have identified altered expression of genes that have been shown to impact neuronal function. The observation that NRBF2 is involved in learning and memory suggests a new mechanism regulating cognition involving the role of this protein in regulating networks related to the function of retinoic acid receptors, protein folding, and quality control.


Assuntos
Proteínas Relacionadas à Autofagia/genética , Encéfalo/metabolismo , Aprendizagem/fisiologia , Memória/fisiologia , Especificidade de Órgãos/genética , Transativadores/genética , Animais , Proteínas Relacionadas à Autofagia/metabolismo , Células Cultivadas , Regulação da Expressão Gênica , Deficiências da Aprendizagem/genética , Deficiências da Aprendizagem/fisiopatologia , Masculino , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/genética , Transtornos da Memória/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Atividade Motora/genética , Atividade Motora/fisiologia , Neurônios/citologia , Neurônios/metabolismo , Transativadores/metabolismo
9.
Cell Physiol Biochem ; 54(3): 438-456, 2020 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-32357291

RESUMO

BACKGROUND/AIMS: Calcium homeostasis plays a crucial role in neuronal development and disease. Calbindin-D9k (CaBP-9k) acts as calcium modulators and sensors in various tissues. However, the neurobiological functions of CaBP-9k are unknown. METHODS: We used CaBP-9k knockout (KO) mice to investigate the roles of these gene in neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. We used anatomical and biochemical approaches to characterize functional abnormalities of the brain in the CaBP-9k KO mice. RESULTS: We found that the brains of CaBP-9k KO mice have increased APP/ß-amyloid, Tau, and α-synuclein accumulation and endoplasmic reticulum (ER) stress-induced apoptosis. Neurons deficient for these CaBP-9k had abnormal intracellular calcium levels and responses. ER stress inhibitor TUDCA reduced ER stress-induced apoptosis and restored ER stress- and apoptosis-related proteins expression to wild-type levels in CaBP-9k KO mice. Furthermore, treatment with TUDCA rescued the abnormal memory and motor behaviors exhibited by older CaBP-9k KO mice. CONCLUSION: Our results suggest that a loss of CaBP-9k may contribute to the onset and progression of neurodegenerative diseases.


Assuntos
Doença de Alzheimer/genética , Apoptose/genética , Calbindinas/genética , Estresse do Retículo Endoplasmático/genética , Doença de Parkinson/genética , Ácido Tauroquenodesoxicólico/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Apoptose/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Calbindinas/metabolismo , Cálcio/metabolismo , Proliferação de Células/genética , Células Cultivadas , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/genética , Camundongos , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Neurônios/metabolismo , Neurônios/patologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , RNA Interferente Pequeno , Fatores de Risco , Ácido Tauroquenodesoxicólico/farmacologia , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo
10.
J Neurosci ; 40(23): 4576-4585, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32341096

RESUMO

An impediment to the development of effective therapies for neurodegenerative disease is that available animal models do not reproduce important clinical features such as adult-onset and stereotypical patterns of progression. Using in vivo magnetic resonance imaging and behavioral testing to study male and female decrepit mice, we found a stereotypical neuroanatomical pattern of progression of the lesion along the limbic system network and an associated memory impairment. Using structural variant analysis, we identified an intronic mutation in a mitochondrial-associated gene (Mrpl3) that is responsible for the decrepit phenotype. While the function of this gene is unknown, embryonic lethality in Mrpl3 knock-out mice suggests it is critical for early development. The observation that a mutation linked to energy metabolism precipitates a pattern of neurodegeneration via cell death across disparate but linked brain regions may explain how stereotyped patterns of neurodegeneration arise in humans or define a not yet identified human disease.SIGNIFICANCE STATEMENT The development of novel therapies for adult-onset neurodegenerative disease has been impeded by the limitations of available animal models in reproducing many of the clinical features. Here, we present a novel spontaneous mutation in a mitochondrial-associated gene in a mouse (termed decrepit) that results in adult-onset neurodegeneration with a stereotypical neuroanatomical pattern of progression and an associated memory impairment. The decrepit mouse model may represent a heretofore undiagnosed human disease and could serve as a new animal model to study neurodegenerative disease.


Assuntos
Variação Genética/genética , Transtornos da Memória/diagnóstico por imagem , Transtornos da Memória/genética , Proteínas Mitocondriais/genética , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/genética , Proteínas Ribossômicas/genética , Fatores Etários , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
11.
Nat Neurosci ; 23(4): 481-486, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32042174

RESUMO

Cognitive decline remains an unaddressed problem for the elderly. We show that myelination is highly active in young mice and greatly inhibited in aged mice, coinciding with spatial memory deficits. Inhibiting myelination by deletion of Olig2 in oligodendrocyte precursor cells impairs spatial memory in young mice, while enhancing myelination by deleting the muscarinic acetylcholine receptor 1 in oligodendrocyte precursor cells, or promoting oligodendroglial differentiation and myelination via clemastine treatment, rescues spatial memory decline during aging.


Assuntos
Envelhecimento/patologia , Doenças Desmielinizantes/patologia , Transtornos da Memória/patologia , Bainha de Mielina/patologia , Envelhecimento/genética , Animais , Doenças Desmielinizantes/complicações , Doenças Desmielinizantes/genética , Doenças Desmielinizantes/metabolismo , Transtornos da Memória/etiologia , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Camundongos , Camundongos Transgênicos , Proteína Básica da Mielina/genética , Proteína Básica da Mielina/metabolismo , Bainha de Mielina/metabolismo , Células Precursoras de Oligodendrócitos/metabolismo , Células Precursoras de Oligodendrócitos/patologia , Fator de Transcrição 2 de Oligodendrócitos/genética , Fator de Transcrição 2 de Oligodendrócitos/metabolismo , Oligodendroglia/metabolismo , Oligodendroglia/patologia
12.
Environ Int ; 136: 105487, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31999974

RESUMO

BACKGROUND: The major components of traffic pollution particulate matter, diesel exhaust particles (DEPs), are airborne ultrafine particles (UFPs). DEPs can enter the central nervous system (CNS), where they may cause neurotoxicity. METHODS: We established murine models with intranasal DEPs instillation in male C57BL/6 and Nlrp3 knock-out (Nlrp3-/-) mice to investigate the effects of DEPs exposure on murine neurobehaviors and related mechanisms. Morris water maze (MWM) tests were performed to evaluate the learning and memory behaviors of mice following DEPs instillation. Metabolomics were assessed using an gas chromatography system coupled to a mass spectrometer. Real-time PCR and immunohistochemistry assays were used to analyze the mRNA and protein expression levels of target genes. Murine microglia, BV2 cells were employed to assay the effects of DEPs exposure in vitro. RESULTS: Intranasal administration of DEPs in mice led to impairment in hippocampal-dependent learning and memory. Moreover, this phenotype was linked to increased number of Iba-1+ microglia and NLRP3 inflammasome, as well as suppression of mitochondrial gene expression in the hippocampus of mice exposed to DEPs. Nlrp3-/- mice were resistant to DEPs-induced learning and memory impairment, concomitant with protection against the suppression of mitochondrial gene expression. Murine microglia cells (BV2) were exposed to DEPs in vitro and taurine was identified as one of the significantly suppressed metabolites in DEPs-treated microglia by metabolomics analysis. Supplementation with taurine efficiently rescued learning, memory and mitochondrial gene expression levels in the hippocampus of DEPs-exposed mice. CONCLUSIONS: Mechanistically, our study revealed that microglia-mediated NLRP3 inflammasome activation plays a deleterious role in DEPs-induced neurotoxicity by inhibiting mitochondrial gene expression. These results shed novel light on the potential value of nutritional supplementation against DEPs-induced neurotoxicity in individuals exposed to severe airborne traffic-related air pollutions.


Assuntos
Transtornos da Memória , Microglia , Proteína 3 que Contém Domínio de Pirina da Família NLR , Emissões de Veículos , Animais , Aprendizagem , Masculino , Memória , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Emissões de Veículos/toxicidade
13.
Hum Mol Genet ; 29(2): 228-237, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31814000

RESUMO

The transient receptor potential vanilloid 1 (TRPV1) protein is a pain receptor that elicits a hot sensation when an organism eats the capsaicin of red chili peppers. This calcium (Ca2+)-permeable cation channel is mostly expressed in the peripheral nervous system sensory neurons but also in the central nervous system (e.g. hippocampus and cortex). Preclinical studies found that TRPV1 mediates behaviors associated with anxiety and depression. Loss of TRPV1 functionality increases expression of genes related to synaptic plasticity and neurogenesis. Thus, we hypothesized that TRPV1 deficiency may modulate Alzheimer's disease (AD). We generated a triple-transgenic AD mouse model (3xTg-AD+/+) with wild-type (TRPV1+/+), hetero (TRPV1+/-) and knockout (TRPV1-/-) TRPV1 to investigate the role of TRPV1 in AD pathogenesis. We analyzed the animals' memory function, hippocampal Ca2+ levels and amyloid-ß (Aß) and tau pathologies when they were 12 months old. We found that compared with 3xTg-AD-/-/TRPV1+/+ mice, 3xTg-AD+/+/TRPV1+/+ mice had memory impairment and increased levels of hippocampal Ca2+, Aß and total and phosphorylated tau. However, 3xTg-AD+/+/TRPV1-/- mice had better memory function and lower levels of hippocampal Ca2+, Aß, tau and p-tau, compared with 3xTg-AD+/+/TRPV1+/+ mice. Examination of 3xTg-AD-derived primary neuronal cultures revealed that the intracellular Ca2+ chelator BAPTA/AM and the TRPV1 antagonist capsazepine decreased the production of Aß, tau and p-tau. Taken together, these results suggested that TRPV1 deficiency had anti-AD effects and promoted resilience to memory loss. These findings suggest that drugs or food components that modulate TRPV1 could be exploited as therapeutics to prevent or treat AD.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Cálcio/metabolismo , Transtornos da Memória/metabolismo , Canais de Cátion TRPV/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Animais , Canais de Cálcio/metabolismo , Capsaicina/análogos & derivados , Capsaicina/farmacologia , Quelantes/farmacologia , Modelos Animais de Doenças , Ácido Egtázico/análogos & derivados , Ácido Egtázico/farmacologia , Hipocampo/metabolismo , Aprendizagem/efeitos dos fármacos , Transtornos da Memória/genética , Camundongos , Camundongos Knockout , Nociceptores/metabolismo , Nociceptores/patologia , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/genética , Proteínas tau/genética
14.
Eur J Pharmacol ; 869: 172857, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31837991

RESUMO

Geniposidic acid (GPA) is an extract from Eucommia ulmoides Oliv. Bark (Eucommiaceae). Accumulating evidences have reported GPA has anti-aging, anti-oxidative stress, anti-inflammatory and neurotrophic effects on neurons. However, whether GPA could alleviate memory deficits in Alzheimer's disease animal models is not clear. We aimed to investigate the effect of GPA treatment on cognitive performance, Aß deposition and glial cells activation in the transgenic mouse model of AD. 6-7 months APP/PS1 mice were given GPA for 90 days; behavioral experiments were executed to estimate the memory and spatial learning abilities of mice, and the mechanism of neuroprotective effect of GPA was investigated with a focus on amyloid-ß deposition, astrocytes and microglia activation and neuroinflammation. GPA treatment significantly improved the spatial learning and memory abilities and also decreased cerebral amyloid-ß deposition in APP/PS1 mice. Via HE staining, we found that GPA could ameliorate histopathological changes in cerebrum. We also found that GPA treatment inhibited the activation of astrocytes and microglia, down-regulated the expression of pro-inflammatory cytokines and iNOS, and up-regulated the expression of anti-inflammatory cytokines and Arg-1. In addition, GPA down-regulated the gene expression of HMGB-1 receptors (TLR2, TLR4 and RAGE) then mediated MyD88, TRAF6 and phospho-ERK1/2, subsequently modulated the expression of key AP-1 and NF-κB family members (c-Fos, c-Jun and p65). The reversal of the pro-inflammatory state suggested GPA can serves as a multi-target candidate by alleviating Aß deposition and neuroinflammation for the auxiliary therapy of Alzheimer's disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Glucosídeos Iridoides/uso terapêutico , Transtornos da Memória/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Anti-Inflamatórios/farmacologia , Astrócitos/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Glucosídeos Iridoides/farmacologia , Memória/efeitos dos fármacos , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Presenilina-1/genética , Transdução de Sinais/efeitos dos fármacos , Aprendizagem Espacial/efeitos dos fármacos , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genética
15.
Neurobiol Aging ; 85: 140-144, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31732218

RESUMO

Age-associated cognitive impairments affect an individual's quality of life and are a growing problem in society. Therefore, therapeutic strategies to treat age-related cognitive decline are needed to enhance the quality of life among the elderly. Activation of the Nr4a family of transcription factors has been closely linked to memory formation and dysregulation of these transcription factors is thought to be associated with age-related cognitive decline. Previously, we have shown that Nr4a transcription can be activated by synthetic bisindole-derived compounds (C-DIM). C-DIM compounds enhance synaptic plasticity and long-term contextual fear memory in young healthy mice. In this study, we show that activation of Nr4a2 by 1,1-bis(3'-Indolyl)-1-(p-chlorophenyl) methane (C-DIM12), enhances long-term spatial memory in young mice and rescues memory deficits in aged mice. These findings suggest that C-DIM activators of Nr4a transcription may be suitable to prevent memory deficits associated with aging.


Assuntos
Envelhecimento Cognitivo , Indóis/farmacologia , Transtornos da Memória/etiologia , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Envelhecimento , Animais , Masculino , Transtornos da Memória/genética , Camundongos Endogâmicos C57BL , Memória Espacial/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos
16.
J Neurosci ; 40(1): 237-254, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31704787

RESUMO

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disability that demonstrates impaired social interactions, communication deficits, and restrictive and repetitive behaviors. ASD has a strong genetic basis and many ASD-associated genes have been discovered thus far. Our previous work has shown that loss of expression of the X-linked gene NEXMIF/KIDLIA is implicated in patients with autistic features and intellectual disability (ID). To further determine the causal role of the gene in the disorder, and to understand the cellular and molecular mechanisms underlying the pathology, we have generated a NEXMIF knock-out (KO) mouse. We find that male NEXMIF KO mice demonstrate reduced sociability and communication, elevated repetitive grooming behavior, and deficits in learning and memory. Loss of NEXMIF/KIDLIA expression results in a significant decrease in synapse density and synaptic protein expression. Consistently, male KO animals show aberrant synaptic function as measured by excitatory miniatures and postsynaptic currents in the hippocampus. These findings indicate that NEXMIF KO mice recapitulate the phenotypes of the human disorder. The NEXMIF KO mouse model will be a valuable tool for studying the complex mechanisms involved in ASD and for the development of novel therapeutics for this disorder.SIGNIFICANCE STATEMENT Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized by behavioral phenotypes. Based on our previous work, which indicated the loss of NEXMIF/KIDLIA was associated with ASD, we generated NEXMIF knock-out (KO) mice. The NEXMIF KO mice demonstrate autism-like behaviors including deficits in social interaction, increased repetitive self-grooming, and impairments in communication and in learning and memory. The KO neurons show reduced synapse density and a suppression in synaptic transmission, indicating a role for NEXMIF in regulating synapse development and function. The NEXMIF KO mouse faithfully recapitulates the human disorder, and thus serves as an animal model for future investigation of the NEXMIF-dependent neurodevelopmental disorders.


Assuntos
Transtorno do Espectro Autista/genética , Modelos Animais de Doenças , Proteínas do Tecido Nervoso/fisiologia , Animais , Ansiedade/genética , Transtorno do Espectro Autista/psicologia , Células Cultivadas , Comportamento Exploratório , Medo , Genes Ligados ao Cromossomo X , Asseio Animal/fisiologia , Hipocampo/citologia , Hipocampo/fisiologia , Relações Interpessoais , Masculino , Aprendizagem em Labirinto , Transtornos da Memória/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Neurônios/fisiologia , Interferência de RNA , RNA Interferente Pequeno/genética , Comportamento Estereotipado/fisiologia , Sinapses/fisiologia , Vocalização Animal
17.
J Neurosci ; 40(1): 220-236, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31685653

RESUMO

Tau is a microtubule-associated protein that becomes dysregulated in a group of neurodegenerative diseases called tauopathies. Differential tau isoforms, expression levels, promoters, and disruption of endogenous genes in transgenic mouse models of tauopathy make it difficult to draw definitive conclusions about the biological role of tau in these models. We addressed this shortcoming by characterizing the molecular and cognitive phenotypes associated with the pathogenic P301L tau mutation (rT2 mice) in relation to a genetically matched transgenic mouse overexpressing nonmutant (NM) 4-repeat (4R) human tau (rT1 mice). Both male and female mice were included in this study. Unexpectedly, we found that 4R NM human tau (hTau) exhibited abnormal dynamics in young mice that were lost with the P301L mutation, including elevated protein stability and hyperphosphorylation, which were associated with cognitive impairment in 5-month-old rT1 mice. Hyperphosphorylation of NM hTau was observed as early as 4 weeks of age, and transgene suppression for the first 4 or 12 weeks of life prevented abnormal molecular and cognitive phenotypes in rT1, demonstrating that NM hTau pathogenicity is specific to postnatal development. We also show that NM hTau exhibits stronger binding to microtubules than P301L hTau, and is associated with mitochondrial abnormalities. Overall, our genetically matched mice have revealed that 4R NM hTau overexpression is pathogenic in a manner distinct from classical aging-related tauopathy, underlining the importance of assaying the effects of transgenic disease-related proteins at appropriate stages in life.SIGNIFICANCE STATEMENT Due to differences in creation of transgenic lines, the pathological properties of the P301L mutation confers to the tau protein in vivo have remained elusive, perhaps contributing to the lack of disease-modifying therapies for tauopathies. In an attempt to characterize P301L-specific effects on tau biology and cognition in novel genetically matched transgenic mouse models, we surprisingly found that nonmutant human tau has development-specific pathogenic properties of its own. Our findings indicate that overexpression of 4-repeat human tau during postnatal development is associated with excessive microtubule binding, which may disrupt important cellular processes, such as mitochondrial dynamics, leading to elevated stability and hyperphosphorylation of tau, and eventual cognitive impairments.


Assuntos
Transtornos da Memória/genética , Doenças Mitocondriais/genética , Proteínas tau/genética , Animais , Células Cultivadas , Feminino , Genes Sintéticos , Hipocampo/citologia , Humanos , Mutação INDEL , Masculino , Aprendizagem em Labirinto , Transtornos da Memória/fisiopatologia , Camundongos , Camundongos Transgênicos , Microtúbulos/fisiologia , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Doenças Mitocondriais/fisiopatologia , Mutação de Sentido Incorreto , Estresse Oxidativo , Fenótipo , Fosforilação , Mutação Puntual , Prosencéfalo/fisiologia , Processamento de Proteína Pós-Traducional , Proteínas Recombinantes , Sequências Repetitivas de Aminoácidos , Especificidade da Espécie , Regulação para Cima , Proteínas tau/biossíntese
18.
Alzheimers Res Ther ; 11(1): 103, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31831047

RESUMO

BACKGROUND: Since both APOE and ABCA7 protein expression may independently reduce neuritic plaque burden and reorganize fibrillar amyloid burden-mediated disruption of functional connectivity in the default mode network, we aimed to investigate the effect of the APOE-ABCA7 interaction on default mode network in Alzheimer's disease. METHODS: Two hundred and eighty-seven individuals with a diagnosis of typical Alzheimer's disease were included in this study. Memory was characterized and compared between APOE-ε4+ carriers and APOE-ε4 non-carriers within ABCA7 rs3764650T allele homozygous carriers and ABCA7 rs3764650G allele carriers, respectively. Two-way analysis of variance was used to identify a significant interaction effect between APOE (APOE-ε4+ carriers versus APOE-ε4 non-carriers) and ABCA7 (ABCA7 rs3764650T allele homozygous versus ABCA7 rs3764650G allele carriers) on memory scores and functional connectivity in each default mode network subsystem. RESULTS: In ABCA7 rs3764650G allele carriers, APOE-ε4+ carriers had lower memory scores (t (159) = - 4.879; P < 0.001) compared to APOE-ε4 non-carriers, but APOE-ε4+ carriers and APOE-ε4 non-carriers did not have differences in memory (P > 0.05) within ABCA7 rs3764650T allele homozygous carriers. There was a significant APOE-ABCA7 interaction effect on the memory (F3, 283 = 4.755, P = 0.030). In the default mode network anchored by the entorhinal seed, the peak neural activity of the cluster that was significantly associated with APOE-ABCA7 interaction effects (P = 0.00002) was correlated with the memory (ρ = 0.129, P = 0.030). CONCLUSIONS: Genetic-biological systems may impact disease presentation and therapy. Clarifying the effect of APOE-ABCA7 interactions on the default mode network and memory is critical to exploring the complex pathogenesis of Alzheimer's disease and refining a potential therapy.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Encéfalo/diagnóstico por imagem , Transtornos da Memória/genética , Rede Nervosa/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/diagnóstico por imagem , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Transtornos da Memória/diagnóstico por imagem , Pessoa de Meia-Idade , Neuroimagem , Testes Neuropsicológicos , Polimorfismo de Nucleotídeo Único
19.
Proc Natl Acad Sci U S A ; 116(51): 25982-25990, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31792184

RESUMO

Retrotransposons compose a staggering 40% of the mammalian genome. Among them, endogenous retroviruses (ERV) represent sequences that closely resemble the proviruses created from exogenous retroviral infection. ERVs make up 8 to 10% of human and mouse genomes and range from evolutionarily ancient sequences to recent acquisitions. Studies in Drosophila have provided a causal link between genomic retroviral elements and cognitive decline; however, in mammals, the role of ERVs in learning and memory remains unclear. Here we studied 2 independent murine models for ERV activation: muMT strain (lacking B cells and antibody production) and intracerebroventricular injection of streptozotocin (ICVI-STZ). We conducted behavioral assessments (contextual fear memory and spatial learning), as well as gene and protein analysis (RNA sequencing, PCR, immunohistochemistry, and western blot assays). Mice lacking mitochondrial antiviral-signaling protein (MAVS) and mice lacking stimulator of IFN genes protein (STING), 2 downstream sensors of ERV activation, provided confirmation of ERV impact. We found that muMT mice and ICVI-STZ mice induced hippocampal ERV activation, as shown by increased gene and protein expression of the Gag sequence of the transposable element intracisternal A-particle. ERV activation was accompanied by significant hippocampus-related memory impairment in both models. Notably, the deficiency of the MAVS pathway was protective against ICVI-STZ-induced cognitive pathology. Overall, our results demonstrate that ERV activation is associated with cognitive impairment in mice. Moreover, they provide a molecular target for strategies aimed at attenuating retroviral element sensing, via MAVS, to treat dementia and neuropsychiatric disorders.


Assuntos
Retrovirus Endógenos/genética , Hipocampo/virologia , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Transtornos da Memória/virologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Comportamento Animal , Encéfalo/patologia , Disfunção Cognitiva , Elementos de DNA Transponíveis , Modelos Animais de Doenças , Retrovirus Endógenos/fisiologia , Regulação da Expressão Gênica , Produtos do Gene gag , Hipocampo/efeitos dos fármacos , Aprendizagem , Masculino , Proteínas de Membrana/metabolismo , Memória , Transtornos da Memória/psicologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estreptozocina/farmacologia
20.
Elife ; 82019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31860442

RESUMO

Loss of the RNA binding protein FMRP causes Fragile X Syndrome (FXS), the most common cause of inherited intellectual disability, yet it is unknown how FMRP function varies across brain regions and cell types and how this contributes to disease pathophysiology. Here we use conditional tagging of FMRP and CLIP (FMRP cTag CLIP) to examine FMRP mRNA targets in hippocampal CA1 pyramidal neurons, a critical cell type for learning and memory relevant to FXS phenotypes. Integrating these data with analysis of ribosome-bound transcripts in these neurons revealed CA1-enriched binding of autism-relevant mRNAs, and CA1-specific regulation of transcripts encoding circadian proteins. This contrasted with different targets in cerebellar granule neurons, and was consistent with circadian defects in hippocampus-dependent memory in Fmr1 knockout mice. These findings demonstrate differential FMRP-dependent regulation of mRNAs across neuronal cell types that may contribute to phenotypes such as memory defects and sleep disturbance associated with FXS.


Assuntos
Transtorno Autístico/metabolismo , Região CA1 Hipocampal/metabolismo , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Transtornos da Memória/genética , Células Piramidais/metabolismo , Animais , Transtorno Autístico/genética , Transtorno Autístico/fisiopatologia , Região CA1 Hipocampal/citologia , Cerebelo/citologia , Cerebelo/metabolismo , Relógios Circadianos/genética , Relógios Circadianos/fisiologia , Modelos Animais de Doenças , Proteína do X Frágil de Retardo Mental/metabolismo , Síndrome do Cromossomo X Frágil/metabolismo , Síndrome do Cromossomo X Frágil/fisiopatologia , Regulação da Expressão Gênica , Humanos , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo
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