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1.
Int J Mol Sci ; 22(10)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34069029

RESUMO

The relationship between the two most prominent neuropathological hallmarks of Alzheimer's Disease (AD), extracellular amyloid-ß (Aß) deposits and intracellular accumulation of hyperphosphorylated tau in neurofibrillary tangles (NFT), remains at present not fully understood. A large body of evidence places Aß upstream in the cascade of pathological events, triggering NFTs formation and the subsequent neuron loss. Extracellular Aß deposits were indeed causative of an increased tau phosphorylation and accumulation in several transgenic models but the contribution of soluble Aß peptides is still controversial. Among the different Aß variants, the N-terminally truncated peptide Aß4-42 is among the most abundant. To understand whether soluble Aß4-42 peptides impact the onset or extent of tau pathology, we have crossed the homozygous Tg4-42 mouse model of AD, exclusively expressing Aß4-42 peptides, with the PS19 (P301S) tau transgenic model. Behavioral assessment showed that the resulting double-transgenic line presented a partial worsening of motor performance and spatial memory deficits in the aged group. While an increased loss of distal CA1 pyramidal neurons was detected in young mice, no significant alterations in hippocampal tau phosphorylation were observed in immunohistochemical analyses.


Assuntos
Doença de Alzheimer/complicações , Peptídeos beta-Amiloides/metabolismo , Modelos Animais de Doenças , Transtornos da Memória/etiologia , Transtornos Motores/etiologia , Mutação , Proteínas tau/genética , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Animais , Comportamento Animal , Feminino , Humanos , Masculino , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transtornos Motores/metabolismo , Transtornos Motores/patologia , Proteínas tau/metabolismo
2.
Food Funct ; 12(9): 3992-4004, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33977955

RESUMO

Learning and memory impairment may result from age-related decline in synaptic plasticity-related proteins in the hippocampus. Therefore, exploration of functional foods capable of ameliorating memory and cognition decline is an interesting endeavor in neuroscience research. We report the effects of Anredera cordifolia (AC) extract on learning and memory deficits in a senescence-accelerated mouse-prone 8 (SAMP8) mouse model, which demonstrate age-related memory deficits and related pathological changes in the brain. After 8 weeks of oral administration of AC extract, the mice were trained in the Novel Object Recognition (NOR) task, and after 7 more weeks, in the Morris Water Maze (MWM) task. Following the completion of behavioral testing, the blood biochemistry parameters, the hippocampal levels of brain-derived neurotropic factor (BDNF), PSD95, and NR2A, and the p-cAMP-response element binding (p-CREB)/CREB ratio were measured. The AC-treated group spent more time exploring the novel objects in the NOR task, and showed faster acquisition and better retention in the MWM task than the negative control (CN) group. In addition, AC enhanced the levels of the aforementioned neuronal plasticity-related proteins, and did not affect the blood biochemistry parameters. Therefore, our data suggest that the AC extract may improve learning and memory without causing any noticeable side effects in the body.


Assuntos
Envelhecimento , Aprendizagem/efeitos dos fármacos , Magnoliopsida , Memória/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação a CREB/metabolismo , Proteína 4 Homóloga a Disks-Large/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Camundongos , Plasticidade Neuronal
3.
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
4.
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
5.
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
6.
Food Funct ; 12(6): 2531-2542, 2021 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-33621295

RESUMO

The aim of this study was to investigate the effects of ethyl acetate extract from Coreopsis tinctoria (EACC) on learning and memory impairment in d-galactose-induced aging mice and the underlying molecular mechanism. The composition of EACC was analyzed by UPLC-MS, and the targets and pathways of EACC to improve learning and memory impairment were predicted and analyzed by the network pharmacology method. A mouse aging model was established by subcutaneous injection of d-galactose in mice, and EACC and piracetam were given to the model mice by gavage to observe their behavioral changes and changes in their SOD and GSH-Px activities in MDA contents in their peripheral blood serum and in the contents of Glu and GABA in their brain tissues. Then the hippocampus of the three mice selected from each of the MOD group and EACC-H group was separated for RT-qPCR assay. The results of the animal experiments showed that EACC could improve the learning and memory impairment of model mice by affecting the level of oxidative stress enzymes in serum and the content of neurotransmitters in the brain tissue. The results of network pharmacology analysis showed that the EACC components corresponded to 74 learning and memory-related targets, of which 13 were enriched in the long-term potentiation pathway. The results of RT-qPCR showed that 12 of the 13 detected targets were consistent with the predicted targets, and 9 of them were located in the NMDA receptor-related pathway of the long-term potentiation process and the pathway played an important regulatory role. It is believed that EACC could improve the learning and memory impairment of d-galactose-induced aging mice by acting on the nine targets Grin1, Grin2a, Camk2a, Camk2b, Kras, Raf1, Mapk1, Mapk3 and Creb to affect the NMDA receptor-related pathway of long-term potentiation.


Assuntos
Coreopsis/química , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Extratos Vegetais/farmacologia , Acetatos , Envelhecimento/efeitos dos fármacos , Envelhecimento/fisiologia , Animais , Modelos Animais de Doenças , Galactose/efeitos adversos , Hipocampo/efeitos dos fármacos , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Estresse Oxidativo/efeitos dos fármacos
7.
Life Sci ; 270: 119079, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33460668

RESUMO

Age-associated memory loss is highly prevalent in the elder population. The inception of neurodegenerative diseases acts as a causative factor for the onset of memory loss in aged individuals. The pathophysiological mechanisms of memory loss associated with the onset of neurodegenerative diseases and normal aging processes share certain similarities as well as differences. The normal age-associated memory loss is attributed to the impairment of calcium metabolism, dysregulated cholesterol metabolism, the prevalence of oxidative stress, inappropriate functioning of hormones as well as genetic factors. Vital information regarding the key biological processes and the druggable targets involved in the onset of memory loss in the elder population has been provided in this article. The genomic and proteomic profiles of key druggable targets retrieved from the experimental evidence, co-expression studies and databases are also presented in this article. The genomic and proteomic information of druggable targets will aid in the identification of therapeutic agents which could effectively regulate the key biological processes involved in the age-associated memory loss.


Assuntos
Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Envelhecimento/metabolismo , Fenômenos Biológicos/efeitos dos fármacos , Cálcio/metabolismo , Colesterol/metabolismo , Genoma , Genômica , Hormônios , Humanos , Doenças Neurodegenerativas/metabolismo , Estresse Oxidativo/fisiologia , Proteômica
8.
Psychopharmacology (Berl) ; 238(3): 877-886, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33404738

RESUMO

BACKGROUND: Memory deficit is a common cognitive comorbid in patients with neuropathic pain that need better treatment. Recent research revealed that nanocurcumin has an antinociceptive action and a protective effect against memory disorders, suggesting its possible effectiveness for the treatment of neuropathic pain and its comorbidity. METHODS: Adult male albino Wistar rats (n = 32) were randomly divided into four experimental groups: CCI+ nanocurcumin, CCI + vehicle, sham + nanocurcumin, and sham + vehicle. Neuropathic pain induced by a chronic constriction injury of the sciatic nerve. Nanocurcumin or vehicle was injected intraperitoneally for 10 days. Behavioral assessment achieved to evaluate pain threshold in the von Frey test and radiant heat test, also spatial learning and memory examined by the Morris water maze (MWM) test. To explore the possible relation, IL-1ß, and TNF-α levels of the hippocampus measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Our data showed that CCI caused neuropathic pain-related behaviors and spatial learning and memory disorders in rats. Chronic treatment with nanocurcumin significantly increased pain threshold (P < 0.001; F = 27.63, F = 20.58), improved spatial memory (P < 0.01; F = 47.37), and decreased the hippocampal levels of IL-1ß (P < 0.001; F = 33.57) and TNF-α (P < 0.01; F = 7.25) in CCI rats. CONCLUSION: Chronic nanocurcumin can ameliorate pain-related behavior, improve spatial learning and memory deficits, and is associated with the reduction of IL-1ß and TNF-α levels in the hippocampus in CCI rats. Nanocurcumin may be potentially providing a therapeutic alternative for the treatment of neuropathic pain and its memory impairment comorbidity.


Assuntos
Analgésicos/uso terapêutico , Curcumina/uso terapêutico , Hipocampo/efeitos dos fármacos , Interleucina-1beta/metabolismo , Neuralgia/tratamento farmacológico , Memória Espacial/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Analgésicos/administração & dosagem , Analgésicos/química , Animais , Comportamento Animal/efeitos dos fármacos , Constrição , Curcumina/administração & dosagem , Curcumina/química , Modelos Animais de Doenças , Hipocampo/metabolismo , Masculino , Transtornos da Memória/complicações , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Nanopartículas/administração & dosagem , Nanopartículas/química , Neuralgia/complicações , Neuralgia/metabolismo , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Wistar , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/lesões
9.
Int J Mol Sci ; 22(3)2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33499311

RESUMO

Currently, there is no cure for Alzheimer's disease (AD) in humans; treatment is symptomatic only. Aging of the population, together with an unhealthy diet and lifestyle, contribute to the steady, global increase of AD patients. This increase creates significant health, societal and economical challenges even for the most developed countries. AD progresses from an asymptomatic stage to a progressively worsening cognitive impairment. The AD cognitive impairment is underpinned by progressive memory impairment, an increasing inability to recall recent events, to execute recently planned actions, and to learn. These changes prevent the AD patient from leading an independent and fulfilling life. Nanotechnology (NT) enables a new, alternative pathway for development of AD treatment interventions. At present, the NT treatments for attenuation of AD memory impairment are at the animal model stage. Over the past four years, there has been a steady increase in publications of AD animal models with a wide variety of original NT treatment interventions, able to attenuate memory impairment. NT therapy development, in animal models of AD, is faced with the twin challenges of the nature of AD, a chronic impairment, unique to human, of the tau protein and A ß peptides that regulate several key physiological brain processes, and the incomplete understanding of AD's aetiology. This paper reviews the state-of-the-art in NT based treatments for AD memory impairment in animal models and discusses the future work for translation to the successful treatment of AD cognitive impairment in human.


Assuntos
Doença de Alzheimer/terapia , Demência/terapia , Transtornos da Memória/terapia , Memória , Nanomedicina/métodos , Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Animais Geneticamente Modificados , Encéfalo/patologia , Disfunção Cognitiva , Demência/metabolismo , Modelos Animais de Doenças , Humanos , Aprendizagem , Transtornos da Memória/metabolismo , Camundongos , Camundongos Transgênicos , Mutação , Nanotecnologia , Ratos , Proteínas tau
10.
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
11.
Eur J Pharmacol ; 893: 173821, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33347827

RESUMO

Memory impairments are frequently reported in patients suffering from brain ischemic diseases. Oxidative/nitrosative stress, synaptic plasticity, and brain-derived neurotrophic factor (BDNF) are involved in the physiopathology of brain ischemia-induced memory disorders. In the present study, the effect of paroxetine as an efficacious antidepressant medication with antioxidant properties was evaluated on passive avoidance memory deficit following cerebral ischemia in rats. Transient occlusion of common carotid arteries was applied to induce ischemia-reperfusion injury in male Wistar rats. Paroxetine (5, 10, 20 mg/kg) was administered intraperitoneally once daily before (for 3 days) or after (for 7 days) the induction of ischemia. A week after ischemia-reperfusion injury, passive avoidance memory, long-term potentiation (LTP), BDNF levels, total antioxidant capacity, the activity of antioxidant enzymes (including catalase, glutathione peroxidase, and superoxide dismutase), the concentration of malondialdehyde (MDA), and nitric oxide (NO) were investigated in the hippocampus. In the passive avoidance test, paroxetine significantly increased the step-through latency and decreased the time spent in the dark compartment. This affirmative function of paroxetine on the passive avoidance memory was accompanied by the improvement of hippocampal LTP and an obvious augmentation in the BDNF contents. Besides, paroxetine caused a significant rise in the total antioxidant capacity and antioxidant enzyme activity; while decreased the hippocampal levels of NO and MDA. It was ultimately attained that paroxetine attenuates cerebral ischemia-induced passive avoidance memory dysfunction in rats by the enhancement of hippocampal synaptic plasticity and BDNF content together with the suppression of oxidative/nitrosative stress.


Assuntos
Antioxidantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Memória/efeitos dos fármacos , Paroxetina/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Masculino , Malondialdeído/metabolismo , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Transtornos da Memória/psicologia , Plasticidade Neuronal/efeitos dos fármacos , Óxido Nítrico/metabolismo , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Traumatismo por Reperfusão/psicologia , Transdução de Sinais
12.
Neurosci Lett ; 740: 135447, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33127446

RESUMO

Alzheimer's disease is an age related progressive neurodegenerative disorder characterized by decline in cognitive functions, such as memory loss and behavioural abnormalities. The present study sought to assess alterations in agmatine metabolism in the beta-amyloid (Aß1-42) Alzheimer's disease mouse model. Aß1-42 injected mice showed impairment of cognitive functioning as evidenced by increased working and reference memory errors in radial arm maze (RAM). This cognitive impairment was associated with a reduction in the agmatine levels and elevation in its degrading enzyme, agmatinase, whereas reduced immunocontent was observed in its synthesizing enzyme arginine decarboxylase expression within hippocampus and prefrontal cortex. Chronic agmatine treatment and its endogenous modulation by l-arginine, or arcaine or aminoguanidine prevented the learning and memory impairment induced by single intracranial Aß1-42 peptide injection. In conclusion, the present study suggests the importance of the endogenous agmatinergic system in ß-amyloid induced memory impairment in mice.


Assuntos
Agmatina/metabolismo , Agmatina/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides , Transtornos da Memória/metabolismo , Fragmentos de Peptídeos , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/psicologia , Animais , Carboxiliases/biossíntese , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/psicologia , Hipocampo/enzimologia , Masculino , Aprendizagem em Labirinto , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/psicologia , Camundongos , Córtex Pré-Frontal/enzimologia , Desempenho Psicomotor/efeitos dos fármacos , Ureo-Hidrolases/metabolismo
13.
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
14.
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
15.
Int J Mol Sci ; 21(24)2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33333883

RESUMO

Huntington's disease (HD) is a genetic neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms, accompanied by massive neuronal degeneration in the striatum. In this study, we utilized solid lipid curcumin particles (SLCPs) and solid lipid particles (SLPs) to test their efficacy in reducing deficits in YAC128 HD mice. Eleven-month-old YAC128 male and female mice were treated orally with SLCPs (100 mg/kg) or equivalent volumes of SLPs or vehicle (phosphate-buffered saline) every other day for eight weeks. Learning and memory performance was assessed using an active-avoidance task on week eight. The mice were euthanized, and their brains were processed using Golgi-Cox staining to study the morphology of medium spiny neurons (MSNs) and Western blots to quantify amounts of DARPP-32, brain-derived neurotrophic factor (BDNF), TrkB, synaptophysin, and PSD-95. We found that both SLCPs and SLPs improved learning and memory in HD mice, as measured by the active avoidance task. We also found that SLCP and SLP treatments preserved MSNs arborization and spinal density and modulated synaptic proteins. Our study shows that SLCPs, as well as the lipid particles, can have therapeutic effects in old YAC128 HD mice in terms of recovering from HD brain pathology and cognitive deficits.


Assuntos
Curcumina/administração & dosagem , Doença de Huntington/metabolismo , Doença de Huntington/psicologia , Lipossomos , Memória/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Animais , Biomarcadores , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/metabolismo , Modelos Animais de Doenças , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Doença de Huntington/etiologia , Aprendizagem/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Camundongos , Camundongos Transgênicos , Neurônios/patologia , Receptor trkB/metabolismo
16.
Nat Commun ; 11(1): 4790, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963242

RESUMO

Preventing aggregation of amyloid beta (Aß) peptides is a promising strategy for the treatment of Alzheimer's disease (AD), and gold nanoparticles have previously been explored as a potential anti-Aß therapeutics. Here we design and prepare 3.3 nm L- and D-glutathione stabilized gold nanoparticles (denoted as L3.3 and D3.3, respectively). Both chiral nanoparticles are able to inhibit aggregation of Aß42 and cross the blood-brain barrier (BBB) following intravenous administration without noticeable toxicity. D3.3 possesses a larger binding affinity to Aß42 and higher brain biodistribution compared with its enantiomer L3.3, giving rise to stronger inhibition of Aß42 fibrillation and better rescue of behavioral impairments in AD model mice. This conjugation of a small nanoparticle with chiral recognition moiety provides a potential therapeutic approach for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/efeitos dos fármacos , Ouro/farmacologia , Transtornos da Memória/tratamento farmacológico , Nanopartículas Metálicas/química , Fragmentos de Peptídeos/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Fragmentos de Peptídeos/metabolismo , Estereoisomerismo
17.
Nat Commun ; 11(1): 4571, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917871

RESUMO

Early therapeutic interventions are essential to prevent Alzheimer Disease (AD). The association of several inflammation-related genetic markers with AD and the early activation of pro-inflammatory pathways in AD suggest inflammation as a plausible therapeutic target. Inflammatory Caspase-1 has a significant impact on AD-like pathophysiology and Caspase-1 inhibitor, VX-765, reverses cognitive deficits in AD mouse models. Here, a one-month pre-symptomatic treatment of Swedish/Indiana mutant amyloid precursor protein (APPSw/Ind) J20 and wild-type mice with VX-765 delays both APPSw/Ind- and age-induced episodic and spatial memory deficits. VX-765 delays inflammation without considerably affecting soluble and aggregated amyloid beta peptide (Aß) levels. Episodic memory scores correlate negatively with microglial activation. These results suggest that Caspase-1-mediated inflammation occurs early in the disease and raise hope that VX-765, a previously Food and Drug Administration-approved drug for human CNS clinical trials, may be a useful drug to prevent the onset of cognitive deficits and brain inflammation in AD.


Assuntos
Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Disfunção Cognitiva/metabolismo , Serpinas/metabolismo , Proteínas Virais/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Comportamento Animal , Disfunção Cognitiva/tratamento farmacológico , Citocinas/metabolismo , Dipeptídeos/sangue , Dipeptídeos/farmacologia , Modelos Animais de Doenças , Encefalite/metabolismo , Encefalite/patologia , Feminino , Humanos , Inflamação/metabolismo , Masculino , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Serpinas/sangue , Serpinas/farmacologia , Memória Espacial/fisiologia , Proteínas Virais/sangue , Proteínas Virais/farmacologia , para-Aminobenzoatos/sangue , para-Aminobenzoatos/farmacologia
18.
PLoS Biol ; 18(8): e3000820, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32866173

RESUMO

Mutations in the gene encoding the microtubule-severing protein spastin (spastic paraplegia 4 [SPG4]) cause hereditary spastic paraplegia (HSP), associated with neurodegeneration, spasticity, and motor impairment. Complicated forms (complicated HSP [cHSP]) further include cognitive deficits and dementia; however, the etiology and dysfunctional mechanisms of cHSP have remained unknown. Here, we report specific working and associative memory deficits upon spastin depletion in mice. Loss of spastin-mediated severing leads to reduced synapse numbers, accompanied by lower miniature excitatory postsynaptic current (mEPSC) frequencies. At the subcellular level, mutant neurons are characterized by longer microtubules with increased tubulin polyglutamylation levels. Notably, these conditions reduce kinesin-microtubule binding, impair the processivity of kinesin family protein (KIF) 5, and reduce the delivery of presynaptic vesicles and postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Rescue experiments confirm the specificity of these results by showing that wild-type spastin, but not the severing-deficient and disease-associated K388R mutant, normalizes the effects at the synaptic, microtubule, and transport levels. In addition, short hairpin RNA (shRNA)-mediated reduction of tubulin polyglutamylation on spastin knockout background normalizes KIF5 transport deficits and attenuates the loss of excitatory synapses. Our data provide a mechanism that connects spastin dysfunction with the regulation of kinesin-mediated cargo transport, synapse integrity, and cognition.


Assuntos
Ácido Glutâmico/metabolismo , Cinesina/metabolismo , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Memória de Curto Prazo , Neurônios/metabolismo , Espastina/deficiência , Tubulina (Proteína)/metabolismo , Potenciais de Ação , Animais , Membrana Celular/metabolismo , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/ultraestrutura , Potenciais Pós-Sinápticos Excitadores , Hipocampo/patologia , Hipocampo/fisiopatologia , Camundongos Knockout , Microtúbulos/metabolismo , Microtúbulos/ultraestrutura , Atividade Motora , Neurônios/patologia , Neurônios/ultraestrutura , Transporte Proteico , Espastina/metabolismo , Sinapses/metabolismo , Sinapses/ultraestrutura , Vesículas Sinápticas/metabolismo
19.
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
20.
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
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