RESUMO
Sporadic Alzheimer's disease (SAD) is the most common form of dementia, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most frequent hereditary ischemic small vessel disease of the brain. Relevant biomarkers or specific metabolic signatures could provide powerful tools to manage these diseases. Therefore, the main goal of this study was to compare the postmortem frontal cortex gray matter, white matter and cerebrospinal fluid (CSF) between a cognitively healthy group and CADASIL and SAD groups. We evaluated 352 individual lipids, belonging to 13 lipid classes/subclasses, using mass spectrometry, and the lipid profiles were subjected to multivariate analysis to discriminate between the dementia groups (CADASIL and SAD) and healthy controls. The main lipid molecular species showing greater discrimination by partial least squares-discriminant analysis (PLS-DA) and a higher significance multivariate correlation (sMC) index were as follows: phosphatidylserine (PS) PS(44:7) and lysophosphatidylethanolamine (LPE) LPE(18:2) in gray matter (GM); phosphatidylethanolamine (PE) PE(32:2) and phosphatidylcholine PC PC(44:6) in white matter (WM), and ether PE (ePE) ePE(38:2) and ether PC (ePC) ePC(34:3) in CSF. Common phospholipid molecular species were obtained in both dementias, such as PS(44:7) and lyso PC (LPC) LPC(22:5) in GM, PE(32:2) in WM and phosphatidic acid (PA) PA(38:5) and PC(42:7) in CFS. Our exploratory study suggests that phospholipids (PLs) involved in neurotransmission alteration, connectivity impairment and inflammation response in GM, WM and CSF are a transversal phenomenon affecting dementias such as CADASIL and SAD independent of the etiopathogenesis, thus providing a possible common prodromal phospholipidic biomarker of dementia.
Assuntos
Doença de Alzheimer/metabolismo , CADASIL/metabolismo , Lobo Frontal/metabolismo , Substância Cinzenta/metabolismo , Tecido Parenquimatoso/metabolismo , Fosfolipídeos/metabolismo , Substância Branca/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/patologia , Autopsia , Biomarcadores/análise , CADASIL/diagnóstico , CADASIL/patologia , Estudos de Casos e Controles , Análise Discriminante , Feminino , Lobo Frontal/patologia , Substância Cinzenta/patologia , Humanos , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Tecido Parenquimatoso/patologia , Fosfolipídeos/química , Fosfolipídeos/classificação , Fosfolipídeos/isolamento & purificação , Substância Branca/patologiaRESUMO
In Alzheimer's disease (AD), amyloid beta (Aß) plaques initiates a cascade of pathological events where the overactivation of N-methyl-d-aspartate receptors (NMDA) by excess glutamate (Glu) triggers oxidative processes that lead to the activation of microglial cells, inflammation, and finally neuronal death. Amaryllidaceae alkaloids exert neuroprotective activities against different neurotoxin-induced injuries in vitro, and although their biological potential is well demonstrated, their neuroprotective activity has not been reported in an in vivo model of AD. The aim of our study was to determine the in vitro and in vivo neuroprotective potential of standardized alkaloidal fractions of Zephyranthes carinata. In this work, the neuroprotective effect of two alkaloidal fractions extracted from Z. carinata (bulbs and leaves) was analyzed in an in vitro excitotoxicity model in order to select the most promising one for subsequent evaluation in a triple transgenic mouse model of AD (3xTg-AD). We found that Z. carinata bulbs protect neurons against a Glu-mediated toxic stimulus in vitro, as evidenced by the decrease in apoptotic nuclei, the reduction in the lipid peroxidation product malondialdehyde and the conservation of dendritic structures. The effects of intraperitoneal administration of Z. carinata bulbs (10 mg/kg) every 12 h for 1 month on 3xTg-AD (18 months old) showed improved learning and spatial memory. Histopathologically, the alkaloidal fraction-treated 3xTg-AD mice exhibited a signiï¬cant reduction in tauopathy and astrogliosis, as well as a signiï¬cant decrease in the proinflammatory marker COX-2 and an increase in pAkt. The results suggest that Z. carinata bulbs provide neuroprotective effects both in vitro and in 3xTg-AD mice by intervening in the inflammatory processes, regulating the aggregation of pair helical filaments (PHFs) and activating survival pathways.
Assuntos
Alcaloides/uso terapêutico , Doença de Alzheimer/prevenção & controle , Amaryllidaceae , Aprendizagem em Labirinto/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Alcaloides/farmacologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Aprendizagem em Labirinto/fisiologia , Memória/efeitos dos fármacos , Memória/fisiologia , Camundongos , Camundongos Transgênicos , Neurônios/metabolismo , Neurônios/patologia , Neuroproteção/fisiologia , Distribuição Aleatória , Ratos , Ratos Wistar , Resultado do TratamentoRESUMO
INTRODUCTION: Alzheimer's disease is the most common form of dementia. It is characterized by histopathological hallmarks such as senile plaques and neurofibrillary tangles, as well as a concomitant activation of microglial cells and astrocytes that release pro-inflammatory mediators such as IL-1ß, iNOS, and COX-2, leading to neuronal dysfunction and death. OBJECTIVE: To evaluate the effect of quercetin on the inflammatory response in the CA1 area of the hippocampus in a 3xTg-AD male and female mice model. MATERIALS AND METHODS: Animals were injected intraperitoneally with quercetin every 48 hours during three months, and we conducted histological and biochemical studies. RESULTS: We found that in quercetin-treated 3xTg-AD mice, reactive microglia and fluorescence intensity of Aß aggregates significantly decreased. GFAP, iNOS, and COX-2 immunoreactivity also decreased and we observed a clear tendency in the reduction of IL-1ß in hippocampal lysates. CONCLUSION: Our work suggests an anti-inflammatory effect of quercetin in the CA1 hippocampal region of aged triple transgenic Alzheimer's disease mice.
Assuntos
Doença de Alzheimer , Antioxidantes/uso terapêutico , Região CA1 Hipocampal/efeitos dos fármacos , Inflamação/tratamento farmacológico , Quercetina/uso terapêutico , Fatores Etários , Doença de Alzheimer/genética , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos TransgênicosRESUMO
Introduction: Alzheimer's disease is the most common form of dementia. It is characterized by histopathological hallmarks such as senile plaques and neurofibrillary tangles, as well as a concomitant activation of microglial cells and astrocytes that release pro-inflammatory mediators such as IL-1ß, iNOS, and COX-2, leading to neuronal dysfunction and death. Objective: To evaluate the effect of quercetin on the inflammatory response in the CA1 area of the hippocampus in a 3xTg-AD male and female mice model. Materials and methods: Animals were injected intraperitoneally with quercetin every 48 hours during three months, and we conducted histological and biochemical studies. Results: We found that in quercetin-treated 3xTg-AD mice, reactive microglia and fluorescence intensity of Aß aggregates significantly decreased. GFAP, iNOS, and COX-2 immunoreactivity also decreased and we observed a clear tendency in the reduction of IL-1ß in hippocampal lysates. Conclusion: Our work suggests an anti-inflammatory effect of quercetin in the CA1 hippocampal region of aged triple transgenic Alzheimer's disease mice.
Introducción. La enfermedad de Alzheimer es la forma más común de demencia; se caracteriza por la presencia de marcadores histopatológicos, como las placas seniles y los ovillos neurofibrilares, así como por una activación concomitante de células microgliales y astrocitos que liberan mediadores proinflamatorios, como IL-1ß, iNOS y COX-2, lo cual conduce a la disfunción y la muerte neuronal. Objetivo. Evaluar el efecto de la quercetina sobre la reacción inflamatoria en el área CA1 del hipocampo en un modelo de ratones 3xTg-AD. Materiales y métodos. Los animales se inyectaron intraperitonealmente con quercetina cada 48 horas durante tres meses, y se hicieron estudios histológicos y bioquímicos. Resultados. Se encontró que en los animales 3xTg-AD tratados con quercetina, la microglía reactiva y la intensidad de fluorescencia de los agregados Aß disminuyeron significativamente, y que hubo una menor reacción de GFAP, iNOS y COX-2, así como una clara tendencia a la reducción de la IL-1 ß en lisados de hipocampo. Conclusión. Los resultados del estudio sugieren un efecto antiinflamatorio de la quercetina en la región CA1 del hipocampo en un modelo en ratón triple trasgénico para la enfermedad de Alzheimer.
Assuntos
Quercetina , Doença de Alzheimer , Astrócitos , MicrogliaRESUMO
Phospholipid alterations in the brain are associated with progressive neurodegeneration and cognitive impairment after acute and chronic injuries. Various types of treatments have been evaluated for their abilities to block the progression of the impairment, but effective treatments targeting long-term post-stroke alterations are not available. In this study, we analyzed changes in the central and peripheral phospholipid profiles in ischemic rats and determined whether a protective monoterpene, Linalool, could modify them. We used an in vitro model of glutamate (125⯵M) excitotoxicity and an in vivo global ischemia model in Wistar rats. Linalool (0.1⯵M) protected neurons and astrocytes by reducing LDH release and restoring ATP levels. Linalool was administered orally at a dose of 25â¯mg/kg every 24â¯h for a month, behavioral tests were performed, and a lipidomic analysis was conducted using mass spectrometry. Animals treated with Linalool displayed faster neurological recovery than untreated ischemic animals, accompanied by better motor and cognitive performances. These results were confirmed by the significant reduction in astrogliosis, microgliosis and COX-2 marker, involving a decrease of 24:0 free fatty acid in the hippocampus. The altered profiles of phospholipids composed of mono and polyunsaturated fatty acids (PC 36:1; 42:1 (24:0/18:1)/LPC 22:6)/LPE 22:6) in the ischemic hippocampus and the upregulation of PI 36:2 and other LCFA (long chain fatty acids) in the serum of ischemic rats were prevented by the monoterpene. Based on these data, alterations in the central and peripheral phospholipid profiles after long-term was attenuated by oral Linalool, promoting a phospholipid homeostasis, related to the recovery of brain function.
Assuntos
Isquemia Encefálica/metabolismo , Hipocampo/metabolismo , Monoterpenos/farmacologia , Doenças Neurodegenerativas/metabolismo , Fármacos Neuroprotetores/farmacologia , Fosfolipídeos/metabolismo , Monoterpenos Acíclicos , Animais , Isquemia Encefálica/complicações , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/patologia , Células Cultivadas , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Modelos Animais de Doenças , Ácido Glutâmico/toxicidade , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/patologia , Distribuição Aleatória , Ratos Wistar , Recuperação de Função Fisiológica/efeitos dos fármacosRESUMO
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is pathologically characterized by the deposition of ß-amyloid (ßA) peptides in senile plaques and neurofibrillary tangles in the brain. Flavonoids have recently been used to prevent and treat a variety of neurodegenerative diseases, but little is known about bioflavonoids. In this study, we evaluate whether a biflavonoid fraction (BF) exerts neuroprotective effects on an aged triple transgenic mouse mode of AD (3xTg-AD). Then, 21-24-month-old 3xTg AD mice were i.p. injected with 25mg/kg of a BF from Garcinia madruno composed of morelloflavone (65%), volkensiflavone (12%), GB 2a (11%), fukugiside (6%) and amentoflavone (0.4%) every 48h for 3 months. The BF treatment reduced ßA deposition in different regions of the brain (the hippocampus, entorhinal cortex and amygdala), reduced ßA1-40 and ßA1-42 levels, BACE1-mediated cleavage of APP (CTFß), tau pathology, astrogliosis and microgliosis in the brains of aged 3xTg-AD mice. Although the BF treatment weakly improved learning, animals treated with BF spent more time in the open arms of the elevated plus maze test and displayed greater risk assessment behavior than the control groups. In summary, the BF reverses histopathological hallmarks and reduces emotional disorders in the 3xTg-AD mouse model, suggesting that the biflavonoids from G. madruno represent a potential natural therapeutic option for AD if its bioavailability is improved.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Biflavonoides/uso terapêutico , Garcinia , Fármacos Neuroprotetores/uso terapêutico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Biflavonoides/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Aprendizagem/efeitos dos fármacos , Masculino , Camundongos Transgênicos , Fármacos Neuroprotetores/farmacologiaRESUMO
Vascular dementia is a transversal phenomenon in different kinds of neurodegenerative diseases involving acute and chronic brain alterations. Specifically, the role of phospholipids in the pathogenesis of dementia remains unknown. In the present study, we explored phospholipid profiles a month postischemia in cognitively impaired rats. The two-vessel occlusion (2-VO) model was used to generate brain parenchyma ischemia in adult male rats confirmed by alterations in myelin, endothelium, astrocytes and inflammation mediator. A lipidomic analysis was performed via mass spectrometry in the hippocampus and serum a month postischemia. We found decreases in phospholipids (PLs) associated with neurotransmission, such as phosphatidylcholine (PC 32:0, PC 34:2, PC 36:3, PC 36:4, and PC 42:1), and increases in PLs implied in membrane structure and signaling, such as lysophosphatidylethanolamine (LPE 18:1, 20:3, and 22:6) and phosphatidylserine (PS 38:4, 36:2, and 40:4), in the hippocampus. Complementarily, PC (PC 34:2, PC 34:3, PC 38:5, and PC 36:5) and ether-PC (ePC 34:1, 34:2, 36:2, 38:2, and 38:3) decreased, while Lyso-PC (LPC 18:0, 18:1, 20:4, 20:5, and LPC 22:6) and phosphatidylinositol (PI 36:2, 38:4, 38:5, and 40:5), as neurovascular state sensors, increased in the serum. Taken together, these data suggest inverse PC/LPC-PI levels as peripheral biomarkers and inverse PC/LPE-PS as a central indicator of postischemic cognitive impairment in rats.
RESUMO
Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder. Several types of treatments have been tested to block or delay the onset of the disease, but none have been completely successful. Diet, lifestyle and natural products are currently the main scientific focuses. Here, we evaluate the effects of oral administration of the monoterpene linalool (25 mg/kg), every 48 h for 3 months, on aged (21-24 months old) mice with a triple transgenic model of AD (3xTg-AD) mice. Linalool-treated 3xTg-AD mice showed improved learning and spatial memory and greater risk assessment behavior during the elevated plus maze. Hippocampi and amygdalae from linalool-treated 3xTg-AD mice exhibited a significant reduction in extracellular ß-amyloidosis, tauopathy, astrogliosis and microgliosis as well as a significant reduction in the levels of the pro-inflammatory markers p38 MAPK, NOS2, COX2 and IL-1ß. Together, our findings suggest that linalool reverses the histopathological hallmarks of AD and restores cognitive and emotional functions via an anti-inflammatory effect. Thus, linalool may be an AD prevention candidate for preclinical studies.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Monoterpenos/uso terapêutico , Memória Espacial/efeitos dos fármacos , Monoterpenos Acíclicos , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Monoterpenos/farmacologia , Proteínas tau/metabolismoRESUMO
Alzheimer's disease (AD) is the most common senile dementia in the world. Although important progress has been made in understanding the pathogenesis of AD, current therapeutic approaches provide only modest symptomatic relief. In this study, we evaluated the neuroprotective effect of quercetin (25 mg/kg) administration via i.p. injection every 48 h for 3 months on aged (21-24 months old) triple transgenic AD model (3xTg-AD) mice. Our data show that quercetin decreases extracellular ß-amyloidosis, tauopathy, astrogliosis and microgliosis in the hippocampus and the amygdala. These results were supported by a significant reduction in the paired helical filament (PHF), ß-amyloid (ßA) 1-40 and ßA 1-42 levels and a decrease in BACE1-mediated cleavage of APP (into CTFß). Additionally, quercetin induced improved performance on learning and spatial memory tasks and greater risk assessment behavior based on the elevated plus maze test. Together, these findings suggest that quercetin reverses histological hallmarks of AD and protects cognitive and emotional function in aged 3xTg-AD mice.