RESUMO
The hyperphosphorylation of tau is a central mechanism in the pathogenesis of Alzheimer's disease (AD). Lithium is a potent inhibitor of glycogen synthase kinase-3beta (GSK3ß), the most important tau kinase in neurons, and may also affect tau phosphorylation by modifying the expression and/or activity of other kinases, such as protein kinase A (PKA), Akt (PKB), and calcium calmodulin kinase-II (CaMKII). The aim of the present study is to determine the effect of chronic lithium treatment on the protein expression of tau and its major kinases in cortical and hippocampal neurons, at distinct working concentrations. Primary cultures of cortical and hippocampal neurons were treated with sub-therapeutic (0.02 mM and 0.2 mM) and therapeutic (2 mM) concentrations of lithium for 7 days. Protein expression of tau and tau-kinases was determined by immunoblotting. An indirect estimate of GSK3ß activity was determined by the GSK3ß ratio (rGSKß). Statistically significant increments in the protein expression of tau and CaMKII were observed both in cortical and hippocampal neurons treated with subtherapeutic doses of lithium. GSK3ß activity was increased in cortical, but decreased in hippocampal neurons. Distinct patterns of changes in the expression of the remaining tau tau-kinases were observed: in cortical neurons, lithium treatment was associated with consistent decrements in Akt and PKA, whereas hippocampal neurons displayed increased protein expression of Akt and decreased PKA. Our results suggest that chronic lithium treatment may yield distinct biological effects depending on the concentration range, with regional specificity. We further suggest that hippocampal neurons may be more sensitive to the effect of lithium, presenting with changes in the expression of tau-related proteins at subtherapeutic doses, which may not be mirrored by the effects observed in cortical neurons.
Assuntos
Hipocampo/efeitos dos fármacos , Cloreto de Lítio/farmacologia , Neurônios/efeitos dos fármacos , Proteínas tau/metabolismo , Animais , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Células Cultivadas , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Glicogênio Sintase Quinase 3 beta/metabolismo , Cloreto de Lítio/administração & dosagem , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos WistarRESUMO
There is increasing evidence suggesting that one of the most relevant pathophysiological features of Alzheimer's disease (AD) is neuroinflammation, which plays an important role in the production and regulation of AD-related proteins (amyloid beta (Aß) and Tau) and exacerbates AD pathology. Neuroinflammation can also be induced by systemic influences (factors from outside the central nervous system). However, the role of systemic inflammation in AD pathophysiology is much less understood. Thus, our main objective in this study was to verify whether the presence of serum cytokines (IL-1ß, IL-6, IL-10, IL-12, and TNF-α) affects different AD biomarkers: Aß1-42 and Tau protein levels, hippocampal volumes (HV), and default mode network functional connectivity (DMN FC) in healthy elderly controls, amnestic mild cognitive impairment (aMCI) patients due to AD, and mild AD patients. To accomplish this, we acquired 3-T MRI, blood, and cerebrospinal fluid (CSF) samples from 42 healthy controls, 55 aMCI patients due to AD, and 33 mild AD patients. Comparing the groups, we found that the mild AD patients presented smaller HV, disrupted DMN FC, and proportionally less IL-1ß than the controls. The aMCI patients only differed from the controls in DMN FC. In intra-group comparison, aMCI and mild AD with detectable levels of cytokines (TNF-α, IL-1ß, IL-10, and IL-12) had decreased DMN FC. On the other hand, patients with detectable levels of IL-10 and IL-12 presented a more favorable AD biomarkers profile (larger HV, more CSF Aß1-42, and less p-Tau), indicating a possible protective role of these ILs. Our findings indicate a possible relationship between systemic inflammation with DMN FC disruption, hippocampal atrophy, and CSF protein levels in the subjects with mild AD and aMCI.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/complicações , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/complicações , Inflamação/líquido cefalorraquidiano , Inflamação/complicações , Idoso , Doença de Alzheimer/diagnóstico por imagem , Estudos de Casos e Controles , Disfunção Cognitiva/diagnóstico por imagem , Citocinas/líquido cefalorraquidiano , Feminino , Humanos , Inflamação/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes NeuropsicológicosRESUMO
OBJECTIVE: The objective of this study was to evaluate brain lithium levels using (7) Li magnetic resonance spectroscopy after 6 weeks of lithium therapy in bipolar depression to test the hypothesis that brain and plasma lithium are correlated. It was also tested whether responders and remitters have different pharmacokinetics, blood and brain lithium levels (ratio) compared with those presenting suboptimal antidepressant improvement. METHOD: Twenty-three patients with bipolar disorder (I and II) during depressive episodes were included and followed up for 6 weeks at the University of Sao Paulo using flexible dose of lithium (450-900 mg/day). Sixteen patients were drug-naïve. At endpoint, patients underwent a (7) Li-MRS scan and brain lithium concentrations were calculated. RESULTS: A significant association between central and peripheral lithium levels was found only in remitters (r = 0.7, P = 0.004) but not in non-remitters (r = -0.12, P = 0.76). Also, brain lithium (but not plasma) was inversely correlated with age (r = -0.46, P = 0.025). Plasma lithium did not correlate with any clinical outcome, lithium dosage or adverse effects. CONCLUSION: These findings suggest that non-remitters may not transport lithium properly to the brain, which may underlie treatment resistance to lithium in BD. Future studies with (7) Li-MRS integrated with the evaluation of blood-brain barrier transport mechanisms and longitudinal clinical outcomes in BD and aging are warranted.
Assuntos
Antimaníacos/farmacocinética , Transtorno Bipolar/metabolismo , Encéfalo/metabolismo , Depressão/metabolismo , Compostos de Lítio/farmacocinética , Adulto , Antimaníacos/uso terapêutico , Transtorno Bipolar/sangue , Transtorno Bipolar/tratamento farmacológico , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Depressão/sangue , Depressão/tratamento farmacológico , Feminino , Humanos , Compostos de Lítio/uso terapêutico , Espectroscopia de Ressonância Magnética/métodos , MasculinoRESUMO
Reduced phospholipase A2 (PLA2) activity and increased phosphorylation of glycogen synthase kinase 3B (GSK3B) participate in the production of beta-amyloid plaques and of neurofibrillary tangles, which are two neuropathological hallmarks of Alzheimer's disease (AD). Experimental evidences suggest a neuroprotective effect of the cholinesterase inhibitor donepezil in the treatment the disease. The aims of the present study were to evaluate in AD patients the effects of treatment with donepezil on PLA2 activity and GSK3B level. Thirty patients with AD were treated during 6 months with 10 mg daily of donepezil. Radio-enzymatic assays were used to measure PLA2 activity and Elisa assays for GSK3B level, both in platelets. Before treatment and after 3 and 6 months on donepezil, AD patients underwent a cognitive assessment and platelet samples were collected. Values were compared to a healthy control group of 42 sex- and age-matched elderly individuals. Before treatment, iPLA2 activity was lower in patients with AD as compared to controls (p < 0.001). At baseline, no differences were found in GSK3B level between both groups. After 3 and 6 months of treatment, we found a significant increase in iPLA2 activity (p = 0.015 and p < 0.001, respectively). iPLA2 increment was related to the cognitive improvement during treatment (p = 0.037). After 6 months, we found an increase in phosphorylated GSK3B (p = 0.02). The present findings suggest two possible mechanisms by which donepezil delays the progression of AD. The increment of iPLA2 activity may reduce the production of beta-amyloid plaques, whereas the phosphorylation of GSK3B inactivates the enzyme, reducing thus the phosphorylation of tau protein.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Plaquetas/enzimologia , Inibidores da Colinesterase/uso terapêutico , Quinase 3 da Glicogênio Sintase/metabolismo , Fosfolipases A2 do Grupo VI/metabolismo , Indanos/uso terapêutico , Piperidinas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/sangue , Análise de Variância , Donepezila , Feminino , Humanos , Masculino , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-Idade , Fosforilação , Fatores de TempoRESUMO
Lithium is a well-established therapeutic option for the acute and long-term management of bipolar disorder and major depression. More recently, based on findings from translational research, lithium has also been regarded as a neuroprotective agent and a candidate drug for disease-modification in certain neurodegenerative disorders, namely, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and, more recently, Parkinson's disease (PD). The putative neuroprotective effects of lithium rely on the fact that it modulates several homeostatic mechanisms involved in neurotrophic response, autophagy, oxidative stress, inflammation, and mitochondrial function. Such a wide range of intracellular responses may be secondary to two key effects, that is, the inhibition of glycogen synthase kinase-3 beta (GSK-3ß) and inositol monophosphatase (IMP) by lithium. In the present review, we revisit the neurobiological properties of lithium in light of the available evidence of its neurotrophic and neuroprotective properties, and discuss the rationale for its use in the treatment and prevention of neurodegenerative diseases.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Compostos de Lítio/farmacologia , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/fisiopatologia , Animais , Humanos , Compostos de Lítio/uso terapêutico , Doenças Neurodegenerativas/fisiopatologia , Fármacos Neuroprotetores/uso terapêuticoRESUMO
OBJECTIVE: Bipolar disorder (BD) likely involves, at a molecular and cellular level, dysfunctions of critical neurotrophic, cellular plasticity and resilience pathways and neuroprotective processes. Therapeutic properties of mood stabilizers are presumed to result from a restoration of the function of these altered pathways and processes through a wide range of biochemical and molecular effects. We aimed to review the altered pathways and processes implicated in BD, such as neurotrophic factors, mitogen-activated protein kinases, Bcl-2, phosphoinositol signaling, intracellular calcium and glycogen synthase kinase-3. METHODS: We undertook a literature search of recent relevant journal articles, book chapter and reviews on neurodegeneration and neuroprotection in BD. Search words entered were 'brain-derived neurotrophic factor,''Bcl-2,''mitogen-activated protein kinases,''neuroprotection,''calcium,''bipolar disorder,''mania,' and 'depression.' RESULTS: The most consistent and replicated findings in the pathophysiology of BD may be classified as follows: i) calcium dysregulation, ii) mitochondrial/endoplasmic reticulum dysfunction, iii) glial and neuronal death/atrophy and iv) loss of neurotrophic/plasticity effects in brain areas critically involved in mood regulation. In addition, the evidence supports that treatment with mood stabilizers; in particular, lithium restores these pathophysiological changes. CONCLUSION: Bipolar disorder is associated with impairments in neurotrophic, cellular plasticity and resilience pathways as well as in neuroprotective processes. The evidence supports that treatment with mood stabilizers, in particular lithium, restores these pathophysiological changes. Studies that attempt to prevent (intervene before the onset of the molecular and cellular changes), treat (minimize severity of these deficits over time), and rectify (reverse molecular and cellular deficits) are promising therapeutic strategies for developing improved treatments for bipolar disorder.
Assuntos
Transtorno Bipolar/metabolismo , Encéfalo/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Antimaníacos/uso terapêutico , Atrofia/metabolismo , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/fisiopatologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cálcio/metabolismo , Humanos , Lítio/uso terapêutico , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Aim of the present study was to investigate the neuroprotective effect of dental pulp cells (DPCs) in in vitro models of Alzheimer and Parkinson disease. Primary cultures of hippocampal and ventral mesencephalic neurons were treated for 24 h with amyloid beta (Abeta(1-42)) peptide 1-42 and 6-OHDA, respectively. DPCs isolated from adult rat incisors were previously cultured in tissue culture inserts and added to the neuron cultures 2 days prior to neurotoxin treatment. Cell viability was assessed by the MTT assay. The co-culture with DPCs significantly attenuated 6-OHDA and Abeta(1-42)-induced toxicity in primary cultures of mesencephalic and hippocampal neurons, and lead to an increase in neuronal viability in untreated cultures, suggesting a neurotrophic effect in both models. Furthermore, human dental pulp cells expressed a neuronal phenotype and produced the neurotrophic factors NGF, GDNF, BDNF, and BMP2 shown by microarray screening and antibody staining for the representative proteins. DPCs protected primary neurons in in vitro models of Alzheimer's and Parkinson's disease and can be viewed as possible candidates for studies on cell-based therapy.
Assuntos
Adrenérgicos/toxicidade , Peptídeos beta-Amiloides/toxicidade , Polpa Dentária/citologia , Polpa Dentária/fisiologia , Neurônios/efeitos dos fármacos , Oxidopamina/toxicidade , Fragmentos de Peptídeos/toxicidade , Análise de Variância , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Técnicas de Cocultura/métodos , Relação Dose-Resposta a Droga , Embrião de Mamíferos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Hipocampo/citologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Mesencéfalo/citologia , Análise em Microsséries/métodos , Proteínas do Tecido Nervoso/metabolismo , Neurônios/fisiologia , Gravidez , RatosRESUMO
BACKGROUND: Previous studies have reported an association between executive dysfunction and the ability to perform activities of daily living (ADL)s among older adults. This study aims to examine the association between executive functions and functional status in a cross-section of older adults with varying degrees of cognitive impairment. METHODS: 89 individuals (mean age 73.8 years) were recruited at a memory clinic in São Paulo, Brazil. Subjects underwent evaluation, and were allocated into three diagnostic groups according to cognitive status: normal controls (NC, n = 32), mild cognitive impairment (MCI, n = 31) and mild Alzheimer's disease (AD, n = 26). Executive functions were assessed with the 25-item Executive Interview (EXIT25), and functional status was measured with the Direct Assessment of Functional Status test (DAFS-R). RESULTS: Significantly different total DAFS-R scores were observed across the three diagnostic groups. Patients with AD performed significantly worse in EXIT25 compared with subjects without dementia, and no significant differences were detected between NC and MCI patients. We found a robust negative correlation between the DAFS-R and the EXIT25 scores (r =-0.872, p < 0.001). Linear regression analyses suggested a significant influence of the EXIT-25 and the CAMCOG on the DAFS-R scores. CONCLUSION: Executive dysfunction and decline in general measures of cognitive functioning are associated with a lower ability to undertake instrumental ADLs. MCI patients showed worse functional status than NC subjects. MCI patients may show subtle changes in functional status that may only be captured by objective measures of ADLs.
Assuntos
Atividades Cotidianas/psicologia , Transtornos Cognitivos/diagnóstico , Testes Neuropsicológicos/estatística & dados numéricos , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Brasil , Transtornos Cognitivos/fisiopatologia , Transtornos Cognitivos/psicologia , Grupos Controle , Avaliação da Deficiência , Feminino , Lobo Frontal/fisiopatologia , Avaliação Geriátrica , Humanos , Modelos Lineares , Masculino , Transtornos da Memória/diagnóstico , Transtornos da Memória/fisiopatologia , Transtornos da Memória/psicologia , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Índice de Gravidade de Doença , Inquéritos e QuestionáriosRESUMO
Phospholipase A(2) (PLA(2)) is a key enzyme in cerebral phospholipid metabolism. Preliminary post-mortem studies have shown that PLA(2) activity is decreased in frontal and parietal areas of the AD brain, which is in accordance with recent (31)P-Magnetic Resonance Spectroscopy evidence of reduced phospholipid turnover in the pre-frontal cortex of moderately demented AD patients. Such abnormality may also be observed in peripheral cells, and reduced PLA(2) activity in platelet membranes of AD patients, and correlates with the severity of dementia. In rat hippocampal slices, PLA(2) has been implicated in mechanisms of synaptic plasticity. In adult rats, the stereotaxic injection of PLA(2) inhibitors in the CA1 area of hippocampus impaired, in a dose-dependent manner, the formation of short- and long-term memory. Additionally, such inhibition resulted in a reduction of the fluidity of hippocampal membranes. In primary cultures of cortical and hippocampal neurons, the inhibition of PLA(2) precluded neurite outgrowth, and the sustained inhibition of the enzyme in mature cultures lead to loss of viability. Taken together, these findings reinforce the involvement of PLA(2) enzymes in neurodevelopment and neurodegeneration processes, and further suggest that reduced PLA(2) activity, probably reducing membrane phospholipids breakdown, may contribute to the memory impairment in AD.