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1.
Mol Med Rep ; 23(5)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33760152

RESUMO

The aim of the present study was to investigate the neuroprotective effects of naringin on the memory impairment of hydrocortisone mice, and to elucidate the potential underlying molecular mechanisms. In the present study, a hydrocortisone model was constructed. Novel object recognition, Morris water maze and step­down tests were performed in order to assess the learning and memory abilities of mice. Hematoxylin and eosin staining was used to observe pathological changes in the hippocampus and hypothalamus. Transmission electron microscopy was used to observe the ultrastructural changes in the hippocampus. Immunohistochemistry was used to detect the expression of ERα and ERß. Western blotting was performed to detect the expression of each protein in the relevant system. It was found that naringin can significantly improve cognitive, learning and memory dysfunction in mice with hydrocortisone memory impairment. In addition, naringin can exert neuroprotective effects through a variety of mechanisms, including amyloid ß metabolism, Tau protein hyperphosphorylation, acetylcholinergic system, glutamate receptor system, oxidative stress and cell apoptosis. Naringin can also affect the expression of phosphorylated­P38/P38, indicating that the neuroprotective effect of naringin may also involve the MAPK/P38 pathway. The results of the present study concluded that naringin can effectively improve the cognitive abilities of mice with memory impairment and exert neuroprotective effects. Thus, naringin may be a promising target drug candidate for the treatment of Alzheimer's disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Flavanonas/farmacologia , Transtornos da Memória/tratamento farmacológico , Proteínas tau/genética , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Humanos , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/genética , Transtornos da Memória/patologia , Redes e Vias Metabólicas/efeitos dos fármacos , Camundongos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/genética
2.
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
3.
Mol Med Rep ; 23(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33537826

RESUMO

Altered expression levels of N­methyl­D­aspartate receptor (NMDAR), a ligand­gated ion channel, have a harmful effect on cellular survival. Hyperthermia is a proven risk factor of transient forebrain ischemia (tFI) and can cause extensive and severe brain damage associated with mortality. The objective of the present study was to investigate whether hyperthermic preconditioning affected NMDAR1 immunoreactivity associated with deterioration of neuronal function in the gerbil hippocampal CA1 region following tFI via histological and western blot analyses. Hyperthermic preconditioning was performed for 1 h before tFI, which was developed by ligating common carotid arteries for 5 min. tFI­induced cognitive impairment under hyperthermia was worse compared with that under normothermia. Loss (death) of pyramidal neurons in the CA1 region occurred fast and was more severe under hyperthermia compared with that under normothermia. NMDAR1 immunoreactivity was not observed in the somata of pyramidal neurons of sham gerbils with normothermia. However, its immunoreactivity was strong in the somata and processes at 12 h post­tFI. Thereafter, NMDAR1 immunoreactivity decreased with time after tFI. On the other hand, NMDAR1 immunoreactivity under hyperthermia was significantly increased in the somata and processes at 6 h post­tFI. The change pattern of NMDAR1 immunoreactivity under hyperthermia was different from that under normothermia. Overall, accelerated tFI­induced neuronal death under hyperthermia may be closely associated with altered NMDAR1 expression compared with that under normothermia.


Assuntos
Isquemia Encefálica/metabolismo , Regulação da Expressão Gênica , Hipocampo/metabolismo , Hipertermia Induzida , Transtornos da Memória/metabolismo , Prosencéfalo/metabolismo , Receptores de N-Metil-D-Aspartato/biossíntese , Animais , Isquemia Encefálica/patologia , Morte Celular , Gerbillinae , Hipocampo/patologia , Masculino , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Neurônios , Prosencéfalo/patologia
4.
Am J Pathol ; 191(1): 144-156, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33339546

RESUMO

Alzheimer disease (AD) is a progressive neurodegenerative disorder and the most common type of dementia worldwide. There is considerable evidence of age-related disruption of proteostasis being responsible for the development of AD. The proteasome is a multicatalytic enzyme complex that degrades both normal and damaged proteins, and an age-related decline in its activity has been implicated in age-related pathologies. Although proteasomal dysfunction is assumed to be a key AD hallmark, it remains unclear whether its role in disease onset is causative or secondary. In this study, we demonstrate that mice with proteasomal dysfunction exhibited memory impairment with associated neuronal loss, accumulation of phosphorylated tau, and activation of endoplasmic reticulum (ER) stress-related apoptosis pathways. Impaired proteasomal activity also activated ER stress-related apoptosis pathways in HT-22, a murine hippocampal neuronal cell line. HT-22 cell death, caused by proteasomal inhibition, was prevented by an inhibitor of c-Jun N-terminal kinase, an ER stress-related molecule. Collective evidence suggests that impaired proteasomal activity alters proteostasis, and subsequent ER stress-mediated pathways play pivotal roles in neuronal loss. Because aging decreases proteasomal function, age-related impairment of proteasomes may be involved in the development and progression of AD in elderly patients.


Assuntos
Encéfalo/patologia , Estresse do Retículo Endoplasmático/fisiologia , Transtornos da Memória/patologia , Neurônios/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Apoptose/fisiologia , Encéfalo/metabolismo , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/metabolismo , Proteínas tau/metabolismo
5.
Biochem Pharmacol ; 184: 114366, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33310049

RESUMO

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders characterized by memory deficits. Although no drug has given promising results, synaptic dysfunction-modulating agents might be considered potential candidates for alleviating this disorder. Pinoresinol, a lignan found in Forsythia suspensa, is a memory-enhancing agent with excitatory synaptic activation. In the present study, we tested whether pinoresinol reduces learning and memory and excitatory synaptic deficits in an amyloid ß (Aß)-induced AD-like mouse model. Pinoresinol enhanced hippocampal long-term potentiation (LTP) through calcium-permeable AMPA receptor, which was mediated by Akt activation. Moreover, pinoresinol ameliorated LTP deficits in amyloid ß (Aß)-treated hippocampal slices via Akt signaling. Oral administration of pinoresinol ameliorated Aß-induced memory deficits without sensory dysfunction. Moreover, AD-like pathology, including neuroinflammation and synaptic deficit, were ameliorated by pinoresinol administration. Collectively, pinoresinol may be a good candidate for AD therapy by modulating synaptic functions.


Assuntos
Furanos/farmacologia , Hipocampo/efeitos dos fármacos , Lignanas/farmacologia , Transtornos da Memória/tratamento farmacológico , Plasticidade Neuronal/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/toxicidade , Animais , Modelos Animais de Doenças , Hipocampo/metabolismo , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Camundongos Endogâmicos , Plasticidade Neuronal/fisiologia , Fragmentos de Peptídeos/toxicidade , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de AMPA/metabolismo
6.
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
7.
Int J Mol Sci ; 21(24)2020 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-33352646

RESUMO

Chronic neuroinflammation is a common pathogenetic link in the development of various neurological and neurodegenerative diseases. Thus, a detailed study of neuroinflammation and the development of drugs that reduce or eliminate the negative effect of neuroinflammation on cognitive processes are among the top priorities of modern neurobiology. N-docosahexanoylethanolamine (DHEA, synaptamide) is an endogenous metabolite and structural analog of anandamide, an essential endocannabinoid produced from arachidonic acid. Our study aims to elucidate the pharmacological activity of synaptamide in lipopolysaccharide (LPS)-induced neuroinflammation. Memory deficits in animals were determined using behavioral tests. To study the effects of LPS (750 µg/kg/day, 7 days) and synaptamide (10 mg/kg/day, 7 days) on synaptic plasticity, long-term potentiation was examined in the CA1 area of acute hippocampal slices. The Golgi-Cox method allowed us to assess neuronal morphology. The production of inflammatory factors and receptors was assessed using ELISA and immunohistochemistry. During the study, functional, structural, and plastic changes within the hippocampus were identified. We found a beneficial effect of synaptamide on hippocampal synaptic plasticity and morphological characteristics of neurons. Synaptamide treatment recovered hippocampal neurogenesis, suppressed microglial activation, and significantly improved hippocampus-dependent memory. The basis of the phenomena described above is probably the powerful anti-inflammatory activity of synaptamide, as shown in our study and several previous works.


Assuntos
Modelos Animais de Doenças , Encefalite/tratamento farmacológico , Etanolaminas/farmacologia , Hipocampo/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Microglia/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Animais , Ácidos Docosa-Hexaenoicos/química , Encefalite/metabolismo , Encefalite/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Potenciação de Longa Duração , Masculino , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Microglia/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia
8.
Nat Commun ; 11(1): 5465, 2020 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-33122660

RESUMO

Eicosapentaenoic acid (EPA), an omega-3 fatty acid, has been widely used to prevent cardiovascular disease (CVD) and treat brain diseases alone or in combination with docosahexaenoic acid (DHA). However, the impact of EPA and DHA supplementation on normal cognitive function and the molecular targets of EPA and DHA are still unknown. We show that acute administration of EPA impairs learning and memory and hippocampal LTP in adult and prepubescent mice. Similar deficits are duplicated by endogenously elevating EPA in the hippocampus in the transgenic fat-1 mouse. Furthermore, the damaging effects of EPA are mediated through enhancing GABAergic transmission via the 5-HT6R. Interestingly, DHA can prevent EPA-induced impairments at a ratio of EPA to DHA similar to that in marine fish oil via the 5-HT2CR. We conclude that EPA exhibits an unexpected detrimental impact on cognitive functions, suggesting that caution must be exercised in omega-3 fatty acid supplementation and the combination of EPA and DHA at a natural ratio is critical for learning and memory and synaptic plasticity.


Assuntos
Cognição/efeitos dos fármacos , Ácido Eicosapentaenoico/efeitos adversos , Neurônios GABAérgicos/efeitos dos fármacos , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Animais , Suplementos Nutricionais/efeitos adversos , Ácidos Docosa-Hexaenoicos/farmacologia , Combinação de Medicamentos , Ácido Eicosapentaenoico/farmacologia , Ácidos Graxos Ômega-3/efeitos adversos , Óleos de Peixe/efeitos adversos , Óleos de Peixe/farmacologia , Humanos , Aprendizagem/efeitos dos fármacos , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Camundongos
9.
PLoS One ; 15(9): e0239581, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32976533

RESUMO

Despite the prevalence of everyday memory failures, little is known about which specific types have the strongest impact on everyday life, and whether their impact changes across adulthood. An investigation of memory failures at different ages is particularly informative to disentangle the age paradox in prospective memory, which seems to suggest that remembering to perform intended actions in everyday life improves with age. Therefore, 58 young adults, 40 middle-aged adults, and 54 elderly adults recorded their memory failures as and when they occurred during a 7-day period, and described how serious and consequential they were. Failures were coded into several subcategories of retrospective memory, prospective memory, and absent-minded lapses. It was prospective memory lapses that were overall the most common, serious and consequential ones. Young adults had substantially more prospective memory failures than the elderly and middle-aged adults who did not differ from each other. A young adult disadvantage still held up when lifestyle differences between young adults and the elderly were taken into account. Our findings support the age-related benefit previously found in naturalistic prospective memory tasks, and suggest that it is robust across various types of prospective memory tasks. The results also suggest that the benefit may result from both young adults having poor everyday prospective memory, compared to any adults of a greater age, and everyday prospective memory being spared from age-related decline between the middle and late adulthood.


Assuntos
Envelhecimento/patologia , Transtornos da Memória/patologia , Rememoração Mental/fisiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Intenção , Masculino , Memória Episódica , Pessoa de Meia-Idade , Testes Neuropsicológicos , Estudos Retrospectivos , Adulto Jovem
10.
Life Sci ; 260: 118338, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32841662

RESUMO

AIMS: Fluoxetine (FLX) is a common selective serotonin reuptake inhibitor, which is used in adolescents with psychiatric disorders. Controversial results have been obtained in different studies about the effects of FLX on cognitive functions. The present study was designed to examine the effects of chronic FLX exposure during adolescence on cognitive function, anxiety-like behaviors, and hippocampal brain-derived neurotrophic factor (BDNF) mRNA expression among adult male and female rats. MAIN METHODS: The sex-dependent effects of FLX chronic administration during adolescence (5 mg/kg/day, gavage) on short-term novel object recognition memory (NORM), anxiety-like behaviors, and BDNF mRNA expression in the hippocampus were examined. NORM and anxiety-like behaviors were assessed by novel object recognition, open field, and elevated plus-maze (EPM) tests, respectively. The expression of BDNF mRNA was also evaluated by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). KEY FINDINGS: The present findings revealed the dysfunction of short-term NORM among the adolescent male and female rats exposed to FLX, while the mRNA expression of BDNF was significantly higher among the males. Moreover, adolescent FLX administration had different effects on the anxiety-like behaviors of the male and female rats. Adolescent FLX treatment also decreased the body weight of the male animals. SIGNIFICANCE: In conclusion, adolescent FLX treatment impairs cognitive functions in both sexes and increases BDNF mRNA expression in the hippocampus of the male animals. FLX administration during adolescence has sex-dependent effects on anxiety-like behaviors. These findings indicate that the impairment of cognitive functions can occur following the adolescent manipulation of the serotonergic system. Therefore, the side effects of chronic FLX administration during adolescence should be more considered.


Assuntos
Ansiedade/tratamento farmacológico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fluoxetina/administração & dosagem , Hipocampo/metabolismo , Transtornos da Memória/tratamento farmacológico , Reconhecimento Psicológico/efeitos dos fármacos , Inibidores de Captação de Serotonina/administração & dosagem , Animais , Ansiedade/patologia , Fator Neurotrófico Derivado do Encéfalo/genética , Feminino , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Masculino , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Ratos , Inibidores de Captação de Serotonina/farmacologia
11.
PLoS One ; 15(7): e0235979, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32706773

RESUMO

Alzheimer's disease (AD) is proposed to be induced by abnormal aggregation of amyloidß in the brain. Here, we designed a brain-permeable peptide nanofiber drug from a fragment of heat shock protein to suppress aggregation of the pathogenic proteins. To facilitate delivery of the nanofiber into the brain, a protein transduction domain from Drosophila Antennapedia was incorporated into the peptide sequence. The resulting nanofiber efficiently suppressed the cytotoxicity of amyloid ßby trapping amyloid ß onto its hydrophobic nanofiber surface. Moreover, the intravenously or intranasally injected nanofiber was delivered into the mouse brain, and improved the cognitive function of an Alzheimer transgenic mouse model. These results demonstrate the potential therapeutic utility of nanofibers for the treatment of AD.


Assuntos
Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/administração & dosagem , Encéfalo/metabolismo , Modelos Animais de Doenças , Transtornos da Memória/prevenção & controle , Nanofibras/administração & dosagem , Placa Amiloide/prevenção & controle , Administração Intranasal , Doença de Alzheimer/etiologia , Doença de Alzheimer/patologia , Animais , Encéfalo/efeitos dos fármacos , Feminino , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Camundongos , Camundongos Transgênicos , Nanofibras/química , Placa Amiloide/etiologia , Placa Amiloide/patologia
12.
Gene ; 754: 144854, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32525045

RESUMO

Alzheimer's disease (AD) is one of the most common forms of neurodegenerative diseases. Aggregation of Aß42 and hyperphosphorylated tau are two major hallmarks of AD. Whether different forms of tau (soluble or hyperphosphorylated) or Aß are the main culprit in the events observed in AD is still under investigation. Here, we examined the effect of wild-type, prone to hyperphosphorylation and hyperphosphorylated tau, and also Aß42 peptide on the brain antioxidant defense system and two mitochondrial genes, Marf (homologous to human MFN2) and Drp1 involved in mitochondrial dynamics in transgenic Drosophila melanogaster. AD is an age associated disease. Therefore, the activity of antioxidant agents, CAT, SOD, and GSH levels and the mRNA levels of Marf and Drp1 were assessed in different time points of the flies lifespan. Reduction in cognitive function and antioxidant activity was observed in all transgenic flies at any time point. The most and the least effect on the eye phenotype was exerted by hyperphosphorylated tau and Aß42, respectively. In addition, the most remarkable alteration in Marf and Drp1 mRNA levels was observed in transgenic flies expressing hyperphosphorylated tau when pan neuronal expression of transgenes was applied. However, when the disease causing gene expression was confined to the mushroom body, Marf and Drp1 mRNA levels alteration was more prominent in tauWT and tauE14 transgenic flies, respectively. In conclusion, in spite of antioxidant deficiency caused by different types of tau and Aß42, it seems that tau exerts more toxic effect on the eye phenotype and mitochondrial genes regulation (Marf and Drp1). Moreover, different mechanisms seem to be involved in mitochondrial genes dysregulation when Aß or various forms of tau are expressed.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Animais Geneticamente Modificados/metabolismo , Drosophila melanogaster/metabolismo , Dinaminas/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , RNA Mensageiro/metabolismo , Proteínas tau/metabolismo , Animais , Animais Geneticamente Modificados/genética , Encéfalo/metabolismo , Drosophila melanogaster/genética , Dinaminas/genética , GTP Fosfo-Hidrolases/genética , Regulação da Expressão Gênica , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/genética , Fosforilação , RNA Mensageiro/genética , Proteínas tau/genética
13.
Neurology ; 94(23): e2424-e2435, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32358221

RESUMO

OBJECTIVE: To determine the predictive power of white matter neuronal networks (i.e., structural connectomes [SCs]) in discriminating memory-impaired patients with temporal lobe epilepsy (TLE) from those with normal memory. METHODS: T1- and diffusion MRI (dMRI), clinical variables, and neuropsychological measures of verbal memory were available for 81 patients with TLE. Prediction of memory impairment was performed with a tree-based classifier (XGBoost) for 4 models: (1) a clinical model including demographic and clinical features, (2) a hippocampal volume (HCV) model, (3) a tract model including 5 temporal lobe white matter association tracts derived from a dMRI atlas, and (4) an SC model based on dMRI. SCs were derived by extracting cortical-cortical connections from a temporal lobe subnetwork with probabilistic tractography. Principal component (PC) analysis was then applied to reduce the dimensionality of the SC, yielding 10 PCs. Multimodal models were also tested combining SCs and tracts with HCV. Each model was trained on 48 patients from 1 epilepsy center and tested on 33 patients from a different center. RESULTS: Multimodal models that included the SC + HCV model yielded the highest classification accuracy (81%; 0.90 sensitivity; 0.67 specificity), outperforming the clinical model (61%; p < 0.001) and HCV model (66%; p < 0.001). In addition, the unimodal SC model (76% accuracy) and tract model (73% accuracy) outperformed the clinical model (p < 0.001) and HCV model (p < 0.001) for classifying patients with TLE with and without memory impairment. Furthermore, the SC identified that short-range temporal-temporal connections were important contributors to memory performance. CONCLUSION: SCs and tract-based models are stronger predictors of memory impairment in TLE than HCVs and clinical variables. However, SCs may provide additional information about local cortical-cortical connectivity contributing to memory that is not captured in large association tracts.


Assuntos
Conectoma , Epilepsia do Lobo Temporal/psicologia , Transtornos da Memória/etiologia , Adulto , Anisotropia , Área Sob a Curva , Imagem de Tensor de Difusão , Escolaridade , Epilepsia do Lobo Temporal/diagnóstico por imagem , Epilepsia do Lobo Temporal/patologia , Feminino , Hipocampo/diagnóstico por imagem , Hipocampo/patologia , Humanos , Masculino , Transtornos da Memória/diagnóstico por imagem , Transtornos da Memória/patologia , Pessoa de Meia-Idade , Modelos Neurológicos , Testes Neuropsicológicos , Tamanho do Órgão , Análise de Componente Principal , Curva ROC , Sensibilidade e Especificidade , Aprendizagem Verbal/fisiologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Adulto Jovem
14.
PLoS One ; 15(4): e0231941, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32315349

RESUMO

Vincristine is a commonly used cytostatic drug for the treatment of leukemia, neuroblastoma and lung cancer, which is known to have neurotoxic properties. The aim of this study was to assess the effects of vincristine, injected directly into the dorsal hippocampus, in spatial memory using the spatial cone field discrimination task. Long Evans rats were trained in the cone field, and after reaching training criterion received bilateral vincristine infusions into the dorsal hippocampus. Vincristine-treated animals presented unilateral or bilateral hippocampal lesions. Animals with bilateral lesions showed lower spatial working and reference memory performance than control animals, but task motivation was unaffected by the lesions. Working and reference memory of animals with unilateral lesions did not differ from animals with bilateral lesions and control animals. In sum, intrahippocampal injection of vincristine caused profound tissue damage in the dorsal hippocampus, associated with substantial cognitive deficits.


Assuntos
Hipocampo/patologia , Transtornos da Memória/patologia , Memória Espacial/efeitos dos fármacos , Vincristina/toxicidade , Animais , Masculino , Transtornos da Memória/induzido quimicamente , Memória de Curto Prazo/efeitos dos fármacos , Ratos , Ratos Long-Evans , Aprendizagem Espacial
15.
J Neurol Neurosurg Psychiatry ; 91(5): 547-559, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32132227

RESUMO

The fornix is a white matter bundle located in the mesial aspect of the cerebral hemispheres, which connects various nodes of a limbic circuitry and is believed to play a key role in cognition and episodic memory recall. As the most prevalent cause of dementia, Alzheimer's disease (AD) dramatically impairs the quality of life of patients and imposes a significant societal burden on the healthcare system. As an established treatment for movement disorders, deep brain stimulation (DBS) is currently being investigated in preclinical and clinical studies for treatment of memory impairment in AD by modulating fornix activity. Optimal target and stimulation parameters to potentially rescue memory deficits have yet to be determined. The aim of this review is to consolidate the structural and functional aspects of the fornix in the context of neuromodulation for memory deficits. We first present an anatomical and functional overview of the fibres and structures interconnected by the fornix. Recent evidence from preclinical models suggests that the fornix is subdivided into two distinct functional axes: a septohippocampal pathway and a subiculothalamic pathway. Each pathway's target and origin structures are presented, followed by a discussion of their oscillatory dynamics and functional connectivity. Overall, neuromodulation of each pathway of the fornix is discussed in the context of evidence-based forniceal DBS strategies. It is not yet known whether driving fornix activity can enhance cognition-optimal target and stimulation parameters to rescue memory deficits have yet to be determined.


Assuntos
Fórnice/anatomia & histologia , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/terapia , Estimulação Encefálica Profunda , Fórnice/patologia , Fórnice/fisiologia , Fórnice/fisiopatologia , Humanos , Transtornos da Memória/patologia , Transtornos da Memória/fisiopatologia , Vias Neurais/anatomia & histologia , Vias Neurais/fisiologia
16.
Cogn Behav Neurol ; 33(1): 16-22, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32132399

RESUMO

BACKGROUND: Verbal memory impairment in individuals with Huntington disease (HD) is well-documented; however, the nature and extent of verbal memory impairment in individuals with premanifest HD (pre-HD) are less understood. OBJECTIVE: To evaluate verbal memory function in individuals with pre-HD by comparing their performance on the California Verbal Learning Test to that of individuals with a clinical diagnosis of HD and that of a demographically similar group of adults with no family history of, or genetic risk for, HD, thereby reducing possible complications of psychiatric difficulties commonly experienced by individuals who are at risk for HD but are gene negative. METHODS: Participant groups included 77 adults with a diagnosis of HD, 23 premanifest gene carriers for HD (pre-HD), and 54 demographically similar, healthy adults. The California Verbal Learning Test-Second Edition (CVLT-II) was used to evaluate the participants' immediate and delayed recall, recognition, learning characteristics, errors, and memory retention. RESULTS: The pre-HD group performed significantly worse than the healthy group, yet significantly better than the HD group, on Short and Long Delay Recall (Free and Cued) and Recognition Discriminability. On Total Immediate Recall, Learning Slope, Semantic Clustering, and Intrusions, the pre-HD group performed similarly to the healthy group and significantly better than the HD group. None of the groups differed in their performance on Repetitions and a measure of retention. CONCLUSIONS: Subtle memory deficits can be observed during the premanifest stage of HD with use of a subset of indices from the CVLT-II.


Assuntos
Doença de Huntington/complicações , Transtornos da Memória/etiologia , Testes de Memória e Aprendizagem/normas , Rememoração Mental/fisiologia , Testes Neuropsicológicos/normas , Aprendizagem Verbal/fisiologia , Adulto , Feminino , Humanos , Doença de Huntington/patologia , Masculino , Transtornos da Memória/patologia , Pessoa de Meia-Idade
17.
Epilepsia ; 61(4): 725-734, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32162320

RESUMO

OBJECTIVE: In patients with temporal lobe epilepsy (TLE) with a nonlesional and nonepileptogenic hippocampus (HC), in order to preserve functionally intact brain tissue, the HC is not resected. However, some patients experience postoperative memory decline, possibly due to disruption of the extrahippocampal memory network and secondary hippocampal volume (HV) loss. The purpose of this study was to determine the extent of hippocampal atrophy ipsilateral and contralateral to the side of the surgery and its relation to memory outcomes. METHODS: Hippocampal volume and verbal as well as visual memory performance were retrospectively examined in 55 patients (mean age ± standard deviation [SD] 30 ± 15 years, 25 female, 31 left) before and 5 months after surgery within the temporal lobe that spared the entire HC. HV was extracted based on prespecified templates, and resection volumes were also determined. RESULTS: HV loss was found both ipsilateral and contralateral to the side of surgery (P < .001). Postoperative left HV loss was a significant predictor of postoperative verbal memory deterioration after left-sided surgery (P < .01). Together with the preoperative verbal memory performance, postoperative left HV explained almost 60% of the variance (P < .0001). However, right HV was not a clear predictor of visual memory performance. Larger resection volumes were associated with smaller postoperative HV, irrespective of side of surgery (left: P < .05, right: P < .01). SIGNIFICANCE: A disruption of the memory network by any resection within the TL, especially within the language-dominant hemisphere, may lead to HC atrophy and memory decline. These findings may further improve the counseling of patients concerning their postoperative memory outcome before TL resections sparing the entire HC.


Assuntos
Epilepsia do Lobo Temporal/cirurgia , Hipocampo/patologia , Transtornos da Memória/etiologia , Procedimentos Neurocirúrgicos/efeitos adversos , Complicações Pós-Operatórias/etiologia , Adolescente , Adulto , Atrofia/patologia , Criança , Feminino , Lateralidade Funcional , Humanos , Masculino , Transtornos da Memória/patologia , Pessoa de Meia-Idade , Complicações Pós-Operatórias/patologia , Estudos Retrospectivos , Lobo Temporal/cirurgia , Adulto Jovem
18.
PLoS One ; 15(2): e0229288, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32078638

RESUMO

The GluD1 gene is associated with susceptibility for schizophrenia, autism, depression, and bipolar disorder. However, the function of GluD1 and how it is involved in these conditions remain elusive. In this study, we generated a Grid1 gene-knockout (GluD1-KO) mouse line with a pure C57BL/6N genetic background and performed several behavioral analyses. Compared to a control group, GluD1-KO mice showed no significant anxiety-related behavioral differences, evaluated using behavior in an open field, elevated plus maze, a light-dark transition test, the resident-intruder test of aggression and sensorimotor gating evaluated by the prepulse inhibition test. However, GluD1-KO mice showed (1) higher locomotor activity in the open field, (2) decreased sociability and social novelty preference in the three-chambered social interaction test, (3) impaired memory in contextual, but not cued fear conditioning tests, and (4) enhanced depressive-like behavior in a forced swim test. Pharmacological studies revealed that enhanced depressive-like behavior in GluD1-KO mice was restored by the serotonin reuptake inhibitors imipramine and fluoxetine, but not the norepinephrine transporter inhibitor desipramine. In addition, biochemical analysis revealed no significant difference in protein expression levels, such as other glutamate receptors in the synaptosome and postsynaptic densities prepared from the frontal cortex and the hippocampus. These results suggest that GluD1 plays critical roles in fear memory, sociability, and depressive-like behavior.


Assuntos
Ansiedade/patologia , Depressão/patologia , Medo , Glutamato Desidrogenase/fisiologia , Relações Interpessoais , Transtornos da Memória/patologia , Transtornos do Comportamento Social/patologia , Animais , Ansiedade/etiologia , Comportamento Animal , Depressão/etiologia , Masculino , Transtornos da Memória/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora , Transtornos do Comportamento Social/etiologia
19.
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
20.
Amino Acids ; 52(3): 371-385, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31902007

RESUMO

The aim of this study was to investigate the effect of the chronic administration of methionine (Met) and/or its metabolite, methionine sulfoxide (MetO), on the behavior and neurochemical parameters of young rats. Rats were treated with saline (control), Met (0.2-0.4 g/kg), MetO (0.05-0.1 g/kg), and/or a combination of Met + MetO, subcutaneously twice a day from postnatal day 6 (P6) to P28. The results showed that Met, MetO, and Met + MetO impaired short-term and spatial memories (P < 0.05), reduced rearing and grooming (P < 0.05), but did not alter locomotor activity (P > 0.05). Acetylcholinesterase activity was increased in the cerebral cortex, hippocampus, and striatum following Met and/or MetO (P < 0.05) treatment, while Na+, K+-ATPase activity was reduced in the hippocampus (P < 0.05). There was an increase in the level of thiobarbituric acid reactive substances (TBARS) in the cerebral cortex in Met-, MetO-, and Met + MetO-treated rats (P < 0.05). Met and/or MetO treatment reduced superoxide dismutase, catalase, and glutathione peroxidase activity, total thiol content, and nitrite levels, and increased reactive oxygen species and TBARS levels in the hippocampus and striatum (P < 0.05). Hippocampal brain-derived neurotrophic factor was reduced by MetO and Met + MetO compared with the control group. The number of NeuN-positive cells was decreased in the CA3 in Met + MetO group and in the dentate gyrus in the Met, MetO, and Met + MetO groups compared to control group (P < 0.05). Taken together, these findings further increase our understanding of changes in the brain in hypermethioninemia by elucidating behavioral alterations, biological mechanisms, and the vulnerability of brain function to high concentrations of Met and MetO.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/complicações , Glicina N-Metiltransferase/deficiência , Hipocampo/patologia , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Metionina/análogos & derivados , Espécies Reativas de Oxigênio/metabolismo , Acetilcolinesterase/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/induzido quimicamente , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Animais , Catalase/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Feminino , Glutationa Peroxidase/deficiência , Glicina N-Metiltransferase/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Transtornos da Memória/metabolismo , Memória de Curto Prazo/efeitos dos fármacos , Metionina/metabolismo , Metionina/toxicidade , Ratos , Ratos Wistar , Memória Espacial/efeitos dos fármacos , Superóxido Dismutase/deficiência , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
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