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1.
Nutrients ; 11(8)2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31408929

RESUMO

The senescence-accelerated prone (SAMP8) mouse model shows age-dependent deterioration in learning and memory and increased oxidative stress in the brain. We previously showed that healthy subjects on a six-week supplementation of a chicken meat hydrolysate (ProBeptigen®/CMI-168) demonstrated enhanced and sustained cognitive performance up until two weeks after the termination of supplementation. In this study, we investigate the effect of ProBeptigen on the progression of age-related cognitive decline. Three-month old SAMP8 mice were orally administered different doses of ProBeptigen (150,300 or 600 mg/kg/day) or saline daily for 13 weeks. Following ProBeptigen supplementation, mice showed lower scores of senescence and improved learning and memory in avoidance tasks. ProBeptigen treatment also increased antioxidant enzyme activity and dopamine level while reducing protein and lipid peroxidation and mitochondrial DNA damage in the brain. Microarray analysis of hippocampus revealed several processes that may be involved in the improvement of cognitive ability by ProBeptigen, including heme binding, insulin growth factor (IGF) regulation, carboxylic metabolic process, oxidation-reduction process and endopeptidase inhibition. Genes found to be significantly altered in both ProBeptigen treated male and female mice include Mup1, Mup17, Mup21, Ahsg and Alb. Taken together, these results suggest a potential anti-aging effect of ProBeptigen in alleviating cognitive deficits and promoting the antioxidant defense system.


Assuntos
Envelhecimento/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Galinhas , Disfunção Cognitiva , Suplementos Nutricionais , Transtornos da Memória , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Encéfalo/metabolismo , Cognição/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Dano ao DNA/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hidrólise , Masculino , Carne/análise , Memória/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/etiologia , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos , Hidrolisados de Proteína/farmacologia , Hidrolisados de Proteína/uso terapêutico , Proteínas/genética , Proteínas/metabolismo
3.
Mol Med Rep ; 20(1): 332-340, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115535

RESUMO

Saikosaponin­D (SSD), which is the main bioactive component in the traditional Chinese medicine Chai Hu (Bupleurum falcatum L), possesses estrogen­like properties and is widely used in treating estrogen­related neurological disorders. The current study aimed to investigate the protective effects of SSD on the fear memory deficit in ovariectomized (OVX) rats and the potential underlying mechanism. SSD treatment significantly prolonged freezing time in OVX rats in a manner similar to that of estradiol (E2), whereas this effect was markedly suppressed by co­administration of ICI182780, a non­selective estrogen receptor (ER) inhibitor. The expression of ERα in the hippocampus of OVX rats was significantly elevated by SSD; however, Erß expression and E2 synthesis were not markedly affected by SSD treatment. Collectively, this study demonstrated that SSD­mediated fear memory improvement in OVX rats may be attributed not to E2 levels or ERß activity, but to ERα activation in the hippocampus.


Assuntos
Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Medo/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Ácido Oleanólico/análogos & derivados , Saponinas/farmacologia , Animais , Bupleurum/química , Estradiol/metabolismo , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor beta de Estrogênio/antagonistas & inibidores , Medo/fisiologia , Feminino , Fulvestranto/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Medicina Tradicional Chinesa , Transtornos da Memória/genética , Transtornos da Memória/patologia , Ácido Oleanólico/farmacologia , Ovariectomia , Ratos , Lobo Temporal/efeitos dos fármacos , Lobo Temporal/patologia
4.
Oxid Med Cell Longev ; 2019: 4032428, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31049134

RESUMO

Tolfenamic acid is a nonsteroidal anti-inflammatory drug with neuroprotective properties, and it alleviates learning and memory deficits in the APP transgenic mouse model of Alzheimer's disease. However, whether tolfenamic acid can prevent motor and memory dysfunction in transgenic animal models of Huntington's disease (HD) remains unclear. To this end, tolfenamic acid was orally administered to transgenic R6/1 mice from 10 to 20 weeks of age, followed by several behavioral tests to evaluate motor and memory function. Tolfenamic acid improved motor coordination in R6/1 mice as tested by rotarod, grip strength, and locomotor behavior tests and attenuated memory dysfunction as analyzed using the novel object recognition test and passive avoidance test. Tolfenamic acid decreased the expression of mutant huntingtin in the striatum of 20-week-old R6/1 mice by inhibiting specificity protein 1 expression and enhancing autophagic function. Furthermore, tolfenamic acid exhibited antioxidant effects in both R6/1 mice and PC12 cell models. Collectively, these results suggest that tolfenamic acid has a good therapeutic effect on R6/1 mice, and may be a potentially useful agent in the treatment of HD.


Assuntos
Antioxidantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Doença de Huntington , Transtornos da Memória , Desempenho Psicomotor/efeitos dos fármacos , ortoaminobenzoatos/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Modelos Animais de Doenças , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Doença de Huntington/genética , Doença de Huntington/metabolismo , Doença de Huntington/patologia , Doença de Huntington/prevenção & controle , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Transtornos da Memória/prevenção & controle , Camundongos , Camundongos Transgênicos , Mutação , Células PC12 , Ratos
5.
J Agric Food Chem ; 67(18): 5122-5134, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-30995031

RESUMO

Neuroinflammation has been intensively demonstrated to be related to various neurodegenerative diseases including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD). A natural polymethoxylated flavone, nobiletin (NOB) has been reported to alleviate oxidative stress, insulin resistance, and obesity. In this study, we evaluated the protection effects of NOB on neuroinflammation and memory deficit. Three-month mice were administrated with NOB by oral gavage every day for 6 weeks (100 mg/kg/day); subsequently mice were injected intraperitoneally with lipopolysaccharide (LPS) for 7 days. Results of behavioral tests revealed that NOB dramatically ameliorated LPS-triggered memory deficit regarding synaptic dysfunctions and neuronal loss. Also, NOB suppressed the microglial activation and proinflammatory cytokine secretion, such as COX-2, IL-1ß, TNF-α, and iNOS. Similarly, upon LPS stimulation, pretreatment NOB diminished the secretion of the proinflammatory cytokines in BV-2 microglia cells by exposure to LPS via modulating MAPKs, PI3K/AKT, and NF-κB signaling pathways. In addition, NOB alleviated LPS-amplified redox imbalance, disturbance of mitochondrial membrane potential (MMP), and dampening of the expression of protein related to mitochondrial respiration. The present study provides compelling evidence that NOB decreased LPS-stimulated neuroinflammation and memory impairment through maintaining cellular oxidative balance and blocking the NF-κB transcriptional pathway, illustrating that the nutritional compound NOB may serve as a potential approach to alleviate neuroinflammation-related diseases.


Assuntos
Flavonas/administração & dosagem , Inflamação/complicações , Transtornos da Memória/prevenção & controle , Quinases de Proteína Quinase Ativadas por Mitógeno/imunologia , NF-kappa B/imunologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Humanos , Inflamação/genética , Inflamação/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Masculino , Transtornos da Memória/etiologia , Transtornos da Memória/genética , Transtornos da Memória/imunologia , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/imunologia , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , NF-kappa B/genética , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
6.
Genes Brain Behav ; 18(5): e12573, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30953414

RESUMO

Guanylyl cyclase C (GC-C) is found in brain regions where dopamine is expressed. We characterized a mouse in which GC-C was knocked out (KO) that was reported to be a model of attention deficit hyperactivity disorder (ADHD). We re-examined this model and controlled for litter effects, used 16 to 23 mice per genotype per sex and assessed an array of behavioral and neurochemical outcomes. GC-C KO mice showed no phenotypic differences from wild-type mice on most behavioral tests, or on striatal or hippocampal monoamines, and notably no evidence of an ADHD-like phenotype. KO mice were impaired on novel object recognition, had decreased tactile startle but not acoustic startle, and females had increased latency on cued training trials in the Morris water maze, but not hidden platform spatial learning trials. Open-field activity showed small differences in females but not males. The data indicate that the GC-C KO mouse with proper controls and sample sizes has a moderate cognitive and startle phenotype but has no ADHD-like phenotype.


Assuntos
Transtornos da Memória/genética , Receptores de Enterotoxina/genética , Animais , Feminino , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Receptores de Enterotoxina/metabolismo , Reflexo de Sobressalto , Percepção do Tato
7.
J Agric Food Chem ; 67(11): 3140-3149, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30813721

RESUMO

Lycium ruthenicum Murr. (LR) is a perennial shrub commonly used as a nutritional food and medicine. Herein, we identified 12 anthocyanins from LR, with petunidin derivatives constituting approximately 97% of the total anthocyanin content. Furthermore, the potential mechanism of anthocyanins exerting neuroprotective effects in d-galactose (d-gal)-treated rats was explored. Behavioral results showed that anthocyanins relieved d-gal-induced memory disorder. Additionally, anthocyanins reduced receptor for advanced glycation end products (RAGE) and suppressed oxidative stress caused by d-gal. Anthocyanins suppressed microgliosis and astrocytosis and reduced the overexpression of nuclear factor kappa B (NF-κB), interleukin-1-ß (IL-1ß), cyclooxygenase-2 (COX-2), and tumor necrosis factor-α (TNF-α). Moreover, anthocyanins lowered C-jun N-terminal kinase ( p-JNK), caspase-3 levels, and the B-cell lymphoma 2-associated X protein/B-cell lymphoma 2 (Bax/Bcl-2) ratio. Thus, anthocyanins from LR attenuated memory disfunction, neuroinflammation, and neurodegeneration caused by d-gal, possibly through the RAGE/NF-κB/JNK pathway, representing a promising, safe candidate for prevention and therapy of neurodegenerative diseases.


Assuntos
Antocianinas/administração & dosagem , Lycium/química , Transtornos da Memória/tratamento farmacológico , Fármacos Neuroprotetores/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Animais , Antocianinas/química , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Feminino , Frutas/química , Galactose/efeitos adversos , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Fármacos Neuroprotetores/química , Extratos Vegetais/química , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
8.
PLoS One ; 14(2): e0211937, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30730976

RESUMO

Initially, the function of the fat mass and obesity associated (Fto) gene seemed to be primarily the regulation of the body weight. Here we show that loss of Fto results in a hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis. In consequence, Fto-/- mice display an anxiety-like behavior and impairments in working memory. Furthermore, differentiation of neurons is affected in the hippocampus. As a cause of these impairments we identified a processing defect of the neurotrophin BDNF which is most likely the result of a reduced expression of MMP-9. Therefore, we propose FTO as a possible new target to develop novel approaches for the treatment of diseases associated with hippocampal disorders. In parallel, we also would like to make the point that any anti-obesity therapy via blocking FTO function can have negative effects on the proper function of the hippocampus.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/metabolismo , Processamento de Proteína Pós-Traducional , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Animais , Ansiedade/genética , Ansiedade/metabolismo , Ansiedade/patologia , Comportamento Animal , Fator Neurotrófico Derivado do Encéfalo/genética , Hipocampo/patologia , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/patologia , Metaloproteinase 9 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/genética , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Memória de Curto Prazo , Camundongos , Camundongos Knockout , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/patologia
9.
Food Chem Toxicol ; 126: 152-161, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30790713

RESUMO

Diisodecyl phthalate (DIDP) is a new type of phthalate used in the coating of pharmaceutical pills and in plastic food wrappers. This research was conducted to investigate whether DIDP could cause learning and memory impairment in mice, using formaldehyde (FA) to construct a positive control. Behavioral analysis showed that oral administration of 15 mg kg-1·d-1 DIDP combined with inhalation of 1 mg m-3 FA led to learning and memory impairment in mice. Histopathological observations of the brain showed that the pathological alterations in the hippocampi. Detection of testosterone (T) and estradiol (E2) levels in the brain and serum showed that E2 levels were associated with learning and memory disorders. Reactive oxygen species (ROS), reduced glutathione (GSH), malondialdehyde (MDA), and 8-hydroxy-2-deoxyguanosine (8-OH-dG) revealed the increased oxidative stress levels. Detection of caspase-3, NF-κB, the phosphorylated cAMP response-element binding protein (p-CREB) and the brain derived neurotrophic factor (BDNF) showed that the protective effect mediated by BDNF, is reduced. However, some of these effects were blocked by the administration of Vitmin E (VitE, 100 mg kg-1·d-1) or 17ß-estradiol (17ß-E2, 100 µg kg-1). These data suggest that DIDP may aggravate the FA-exposure-induced learning and memory impairment in mice, and that 17ß-E2 could be utilized to avoid these adverse effects.


Assuntos
Formaldeído/toxicidade , Transtornos da Memória/etiologia , Ácidos Ftálicos/toxicidade , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Aprendizagem/efeitos dos fármacos , /metabolismo , Masculino , Malondialdeído/metabolismo , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo
10.
Continuum (Minneap Minn) ; 25(1): 14-33, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30707185

RESUMO

PURPOSE OF REVIEW: Alzheimer disease (AD) is the most common cause of late-onset dementia. This article describes the epidemiology, genetic and environmental risk factors, clinical diagnosis, biomarkers, and treatment of late-onset AD, defined by age of onset of 65 years or older. RECENT FINDINGS: An estimated 5.7 million Americans are living with AD dementia, with the number of affected individuals growing rapidly because of an aging population. Vascular risk factors, sleep disorders, and traumatic brain injury are associated with an increased risk of AD, while increased cognitive and physical activity throughout the lifespan reduce the risk of disease. The primary genetic risk factor for late-onset AD is the apolipoprotein E (APOE) ε4 allele. AD typically presents with early and prominent episodic memory loss, although this clinical syndrome is neither sensitive nor specific for underlying AD neuropathology. Emerging CSF and imaging biomarkers can now detect the key neuropathologic features of the disease (amyloid plaques, neurofibrillary tangles, and neurodegeneration) in living people, allowing for characterization of patients based on biological measures. A comprehensive treatment plan for AD includes use of symptomatic medications, optimal treatment of comorbid conditions and neuropsychiatric symptoms, counseling about safety and future planning, and referrals to community resources. SUMMARY: AD is very common in older neurologic patients. Neurologists should set the standard for the diagnosis and care of patients with AD and should be familiar with emerging biomarkers that have transformed AD research and are primed to enter the clinical arena.


Assuntos
Doença de Alzheimer/genética , Cognição/fisiologia , Disfunção Cognitiva/genética , Transtornos de Início Tardio/genética , Atividades Cotidianas , Humanos , Transtornos da Memória/genética
11.
Neurobiol Aging ; 76: 151-161, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30716540

RESUMO

Similar to elderly humans, aged outbred Long-Evans rats exhibit individual differences in memory abilities, including a subset of aged rats that maintain memory function on par with young adults. Such individuals provide a basis for investigating mechanisms of resilience to age-related decline. The present study examined hippocampal gene expression in young adults and aged rats with preserved memory function under behavioral task conditions well established for assessing information processing central to the formation of episodic memory. Although behavioral measures and hippocampal gene induction associated with neural activity and synaptic plasticity were similar across age groups, a marker for inhibitory interneuron function in the hippocampal formation was distinctively increased only in aged rats but not in young adults. Because heightened hippocampal neural activity is associated with age-related memory impairment across species, including rats, monkeys, and humans, this finding may represent an adaptive homeostatic adjustment necessary to maintain neural plasticity and memory function in aging.


Assuntos
Envelhecimento/genética , Envelhecimento/psicologia , Sinais (Psicologia) , Expressão Gênica , Hipocampo/fisiologia , Transtornos da Memória/genética , Transtornos da Memória/psicologia , Memória/fisiologia , Inibição Neural/fisiologia , Animais , Comportamento Animal , Interneurônios/fisiologia , Masculino , Plasticidade Neuronal/genética , Ratos Long-Evans
12.
Brain ; 142(3): 787-807, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30668640

RESUMO

Epigenetic dysregulation, which leads to the alteration of gene expression in the brain, is suggested as one of the key pathophysiological bases of ageing and neurodegeneration. Here we found that, in the late-stage familial Alzheimer's disease (FAD) mouse model, repressive histone H3 dimethylation at lysine 9 (H3K9me2) and euchromatic histone methyltransferases EHMT1 and EHMT2 were significantly elevated in the prefrontal cortex, a key cognitive region affected in Alzheimer's disease. Elevated levels of H3K9me2 were also detected in the prefrontal cortex region of post-mortem tissues from human patients with Alzheimer's disease. Concomitantly, H3K9me2 at glutamate receptors was increased in prefrontal cortex of aged FAD mice, which was linked to the diminished transcription, expression and function of AMPA and NMDA receptors. Treatment of FAD mice with specific EHMT1/2 inhibitors reversed histone hyper-methylation and led to the recovery of glutamate receptor expression and excitatory synaptic function in prefrontal cortex and hippocampus. Chromatin immunoprecipitation-sequencing (ChIP-seq) data indicated that FAD mice exhibited genome-wide increase of H3K9me2 enrichment at genes involved in neuronal signalling (including glutamate receptors), which was reversed by EHMT1/2 inhibition. Moreover, the impaired recognition memory, working memory, and spatial memory in aged FAD mice were rescued by the treatment with EHMT1/2 inhibitors. These results suggest that disrupted epigenetic regulation of glutamate receptor transcription underlies the synaptic and cognitive deficits in Alzheimer's disease, and targeting histone methylation enzymes may represent a novel therapeutic strategy for this prevalent neurodegenerative disorder.


Assuntos
Doença de Alzheimer/metabolismo , Antígenos de Histocompatibilidade/fisiologia , Histona-Lisina N-Metiltransferase/fisiologia , Animais , Deleção Cromossômica , Cognição/fisiologia , Transtornos Cognitivos/genética , Disfunção Cognitiva/metabolismo , Metilação de DNA/genética , Modelos Animais de Doenças , Epigênese Genética/genética , Hipocampo/metabolismo , Antígenos de Histocompatibilidade/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Humanos , Lisina/genética , Transtornos da Memória/genética , Metilação , Camundongos , Camundongos Transgênicos , Córtex Pré-Frontal/metabolismo , Sinapses/metabolismo
13.
Nat Neurosci ; 22(2): 205-217, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30664766

RESUMO

Nuclear receptor corepressor 1 (NCOR1) and NCOR2 (also known as SMRT) regulate gene expression by activating histone deacetylase 3 through their deacetylase activation domain (DAD). We show that mice with DAD knock-in mutations have memory deficits, reduced anxiety levels, and reduced social interactions. Mice with NCOR1 and NORC2 depletion specifically in GABAergic neurons (NS-V mice) recapitulated the memory deficits and had reduced GABAA receptor subunit α2 (GABRA2) expression in lateral hypothalamus GABAergic (LHGABA) neurons. This was associated with LHGABA neuron hyperexcitability and impaired hippocampal long-term potentiation, through a monosynaptic LHGABA to CA3GABA projection. Optogenetic activation of this projection caused memory deficits, whereas targeted manipulation of LHGABA or CA3GABA neuron activity reversed memory deficits in NS-V mice. We describe de novo variants in NCOR1, NCOR2 or HDAC3 in patients with intellectual disability or neurodevelopmental disorders. These findings identify a hypothalamus-hippocampus projection that may link endocrine signals with synaptic plasticity through NCOR-mediated regulation of GABA signaling.


Assuntos
Região CA3 Hipocampal/metabolismo , Neurônios GABAérgicos/metabolismo , Hipotálamo/metabolismo , Transtornos da Memória/genética , Memória/fisiologia , Correpressor 1 de Receptor Nuclear/genética , Correpressor 2 de Receptor Nuclear/genética , Animais , Bases de Dados Factuais , Potenciais Pós-Sinápticos Excitadores/genética , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Transtornos da Memória/metabolismo , Camundongos , Camundongos Transgênicos , Vias Neurais/metabolismo , Plasticidade Neuronal/fisiologia , Correpressor 1 de Receptor Nuclear/metabolismo , Correpressor 2 de Receptor Nuclear/metabolismo , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo
14.
Neuron ; 101(5): 920-937.e13, 2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30685224

RESUMO

The proper interactions between blood vessels and neurons are critical for maintaining the strength of neural circuits and cognitive function. However, the precise molecular events underlying these interactions remain largely unknown. Here, we report that the selective knockout of semaphorin 3G (Sema3G) in endothelial cells impaired hippocampal-dependent memory and reduced dendritic spine density in CA1 neurons in mice; these effects were reversed after restoration of Sema3G levels in the hippocampus by AAV transfection. We further show that Sema3G increased excitatory synapse density via neuropilin-2/PlexinA4 signaling and through activation of Rac1. These results provide the first evidence that, in the central nervous system, endothelial Sema3G serves as a vascular-derived synaptic organizer that regulates synaptic plasticity and hippocampal-dependent memory. Our findings highlight the role of vascular endothelial cells in regulating cognitive function through intercellular communication with neurons in the hippocampus.


Assuntos
Endotélio Vascular/metabolismo , Hipocampo/metabolismo , Transtornos da Memória/metabolismo , Plasticidade Neuronal , Semaforinas/metabolismo , Animais , Células Cultivadas , Feminino , Células HEK293 , Hipocampo/fisiologia , Humanos , Masculino , Transtornos da Memória/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neuropilina-2/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Semaforinas/genética , Sinapses/metabolismo , Sinapses/fisiologia
15.
Mol Neurobiol ; 56(2): 1211-1220, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29881943

RESUMO

Previous studies showed that the leukotrienes pathway is increased in human tauopathy and that its manipulation may modulate the onset and development of the pathological phenotype of tau transgenic mice. However, whether interfering with leukotrienes biosynthesis is beneficial after the behavioral deficits and the neuropathology have fully developed in these mice is not known. To test this hypothesis, aged tau transgenic mice were randomized to receive zileuton, a specific leukotriene biosynthesis inhibitor, or vehicle starting at 12 months of age for 16 weeks and then assessed in their functional and pathological phenotype. Compared with baseline, we observed that untreated tau mice had a worsening of their memory and spatial learning. By contrast, tau mice treated with zileuton had a reversal of these deficits and behaved in an undistinguishable manner from wild-type mice. Leukotriene-inhibited tau mice had an amelioration of synaptic integrity, lower levels of neuroinflammation, and a significant reduction in tau phosphorylation and pathology, which was secondary to an involvement of the cdk5 kinase pathway. Taken together, our findings represent the first demonstration that the leukotriene biosynthesis is functionally involved at the later stages of the tau pathological phenotype and represents an ideal target with viable therapeutic potential for treating human tauopathies.


Assuntos
Encéfalo/metabolismo , Quinase 5 Dependente de Ciclina/metabolismo , Leucotrienos/biossíntese , Transtornos da Memória/genética , Transdução de Sinais/fisiologia , Aprendizagem Espacial/fisiologia , Proteínas tau/genética , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Hidroxiureia/análogos & derivados , Hidroxiureia/farmacologia , Antagonistas de Leucotrienos/farmacocinética , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Camundongos , Camundongos Transgênicos , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Aprendizagem Espacial/efeitos dos fármacos , Tauopatias/genética , Tauopatias/metabolismo , Tauopatias/patologia , Proteínas tau/metabolismo
16.
Curr Stem Cell Res Ther ; 14(2): 184-190, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30033876

RESUMO

BACKGROUND AND OBJECTIVE: Alzheimer's Disease (AD) is a progressive neurodegenerative disorder with consequent cognitive impairment and behavioral deficits. AD is characterized by loss of cholinergic neurons and the presence of beta-amyloid protein deposits. Stem cell transplantation seems to be a promising strategy for regeneration of defects in the brain. METHOD: One of the suitable type of stem cells originated from fetal membrane is Chorion-derived Mesenchymal Stem Cells (C-MSCs). MSCs were isolated from chorion and characterized by Flowcytometric analysis. Then C-MSCs labeled with DiI were transplanted into the STZ induced Alzheimer disease model in rat. RESULTS: Nissl staining and behavior test were used to assess the efficacy of the transplanted cells. Phenotypic and Flowcytometric studies showed that isolated cells were positive for mesenchymal stem cell marker panel with spindle like morphology. CONCLUSION: Learning and memory abilities were not improved after stem cell transplantation. C-MSCs transplantation can successfully engraft in injured site but the efficacy and function of transplanted cells were not clinically satisfied.


Assuntos
Doença de Alzheimer/terapia , Transtornos da Memória/terapia , Transplante de Células-Tronco Mesenquimais , Neurônios/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Encéfalo/fisiopatologia , Diferenciação Celular/genética , Córion/citologia , Modelos Animais de Doenças , Hipocampo , Humanos , /fisiopatologia , Transtornos da Memória/genética , Transtornos da Memória/fisiopatologia , Testes de Memória e Aprendizagem , Células-Tronco Mesenquimais/citologia , Neurônios/patologia , Ratos
17.
Artigo em Inglês | MEDLINE | ID: mdl-29958859

RESUMO

Social behavior is a fundamental aspect of our own species, a feature without which our society would not function. There are numerous human brain disorders associated with abnormal social behavior, among them are the autism spectrum disorders whose causal factors include a genetic component. Environmental factors, including drugs of abuse such as alcohol, also contribute to numerous abnormalities related to social behavior. Several such disorders have been modeled using laboratory animals. Perhaps one of the newest among them is the zebrafish. However, the paucity of standardized behavioral assays specifically developed for the zebrafish have hindered progress. Here, we present a newly developed zebrafish behavioral paradigm, the three-chamber social choice task. This task, which was adapted from a murine model, assesses sociality and social novelty preference in zebrafish in three phases: habituation, phase-I to evaluate sociality, and phase-II to quantify social novelty preference. Test fish are placed in the middle chamber, while conspecifics are introduced to the flanking chambers during phase-I and II. Both male and female zebrafish displayed sociality (preference for conspecifics) during phase-I and social novelty preference (preference for unfamiliar conspecifics) during phase-II. We found the paradigm to be able to detect both environmentally (alcohol) as well as genetically (targeted knock out of sam2) induced alterations of behavioral phenotypes. Although ethanol-treated fish displayed similar levels of sociality to those of control (not alcohol exposed) male and female zebrafish, they were found to exhibit significantly impaired social novelty preference, a finding compatible with altered motivational or perhaps mnemonic processes. Moreover, we found that knock out of sam2, previously shown to lead to emotional dysregulation, also disrupted social novelty preference, while leaving sociality relatively intact. We conclude that our novel behavioral paradigm is appropriate for the modeling and quantification of social behavior deficits in zebrafish.


Assuntos
Depressores do Sistema Nervoso Central/toxicidade , Comportamento de Escolha , Etanol/toxicidade , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/genética , Mutação/genética , Comportamento Social , Aminopeptidases/genética , Animais , Animais Geneticamente Modificados , Comportamento de Escolha/efeitos dos fármacos , Comportamento de Escolha/fisiologia , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Feminino , Masculino , Estatísticas não Paramétricas , Peixe-Zebra , Proteínas de Peixe-Zebra/genética
18.
Mol Neurobiol ; 56(5): 3451-3462, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30128653

RESUMO

Aging is characterized by progressive memory decline that can lead to dementia when associated with neurodegeneration. Here, we show in mice that aging-related memory decline involves defective biogenesis of microRNAs (miRNAs), in particular miR-183/96/182 cluster, resulting from increased protein phosphatase 1 (PP1) and altered receptor SMAD (R-SMAD) signaling. Correction of the defect by miR-183/96/182 overexpression in hippocampus or by environmental enrichment that normalizes PP1 activity restores memory in aged animals. Regulation of miR-183/96/182 biogenesis is shown to involve the neurodegeneration-related RNA-binding proteins TDP-43 and FUS. Similar alterations in miR-183/96/182, PP1, and R-SMADs are observed in the brains of patients with amyotrophic lateral sclerosis (ALS) or frontotemporal lobar degeneration (FTLD), two neurodegenerative diseases with pathological aggregation of TDP-43. Overall, these results identify new mechanistic links between miR-183/96/182, PP1, TDP-43, and FUS in age-related memory deficits and their reversal.


Assuntos
Envelhecimento/patologia , Transtornos da Memória/complicações , Transtornos da Memória/genética , MicroRNAs/biossíntese , Degeneração Neural/complicações , Degeneração Neural/genética , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/patologia , Animais , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Transtornos Cognitivos/genética , Transtornos Cognitivos/patologia , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Proteína Fosfatase 1/metabolismo , Proteína FUS de Ligação a RNA/metabolismo , Proteínas Smad/metabolismo
19.
Radiology ; 290(1): 167-176, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30351255

RESUMO

Purpose To evaluate the association between the global fibrillary amyloid-ß pathology and the basal forebrain connectivity at rest in cognitively intact older adults at risk for Alzheimer disease. Materials and Methods This retrospective study was approved by the local ethics committee and written informed consent was obtained from all participants. Resting-state functional connectivity (RSFC) of anterior and posterior basal forebrain seeds was investigated, as well as PET-measured global amyloid-ß load by using standardized uptake value ratio (SUVR) in 267 older cognitively intact individuals with subjective memory complaints (age range, 70-85 years; overall mean age, 75.8 years; 167 women [mean age, 75.9 years] and 100 men [mean age, 75.8 years]). The participants were from the Investigation of Alzheimer's Predictors in Subjective Memory Complainers (INSIGHT-preAD) cohort (date range, 2013-present). The relationship between SUVR and the basal forebrain RSFC was assessed, followed by the effects of apolipoprotein E (APOE) genotype and sex on the basal forebrain RSFC. Results Higher SUVR values correlated with lower posterior basal forebrain RSFC in the hippocampus and the thalamus (Pearson r =-0.23; P <.001 corrected for familywise error [FWE]). Both sex and APOE genotype impacted the associations between basal forebrain RSFC and the global amyloid deposition (t values >3.59; P <.05 corrected for FWE). Conclusion Data indicate a distinct in vivo association between posterior basal forebrain dynamics and global fibrillary amyloid-ß pathology in cognitively intact older adults with subjective memory complaints; both apolipoprotein E and sex moderate such association. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Caspers in this issue.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Prosencéfalo Basal , Química Encefálica/fisiologia , Transtornos da Memória , Rede Nervosa , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/química , Apolipoproteínas E/genética , Prosencéfalo Basal/química , Prosencéfalo Basal/diagnóstico por imagem , Prosencéfalo Basal/metabolismo , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Transtornos da Memória/diagnóstico por imagem , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/metabolismo , Tomografia por Emissão de Pósitrons , Descanso/fisiologia , Estudos Retrospectivos
20.
Food Funct ; 10(1): 325-332, 2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-30574980

RESUMO

Theanine (γ-glutamylethylamide), an amino acid in tea, is a putative neuroprotective and antioxidant compound capable of improving lifespan and cognitive function. Because we previously reported cognitive dysfunction in klotho mutant mice via down-regulation of janus kinase 2 (JAK2) and signal transducer and activator of transcription3 (STAT3), M1 muscarinic cholinergic receptor (M1 mAChR), and ERK signaling, we, therefore, investigated whether self-administration of theanine affects memory dysfunction in response to klotho gene depletion in mice, and whether theanine modulates the JAK2/STAT3, M1 mAChR, and ERK signaling network. Theanine significantly attenuated memory impairments in klotho mutant mice. Moreover, theanine self-administration significantly attenuated inhibitions of JAK2/STAT3 phosphorylation, M1 mAChR expression, and ERK1/2 phosphorylation in the hippocampus of klotho mutant mice. Consistently, AG490, a JAK2/STAT3 inhibitor, dicyclomine, an M1 mAChR antagonist, or U0126, an ERK1/2 inhibitor, significantly counteracted theanine-induced attenuation of memory impairment induced by klotho gene depletion in mice. Our study suggests that theanine attenuates memory impairments in a genetic aging model via up-regulation of JAK2/STAT3, M1 mAChR, and ERK signaling.


Assuntos
Glucuronidase/deficiência , Glutamatos/administração & dosagem , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/genética , Animais , Feminino , Glucuronidase/genética , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Masculino , Memória/efeitos dos fármacos , Transtornos da Memória/metabolismo , Camundongos , Camundongos Knockout , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo
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