RESUMO
Alzheimer's disease (AD) is a progressive, age-dependent neurodegenerative disorder affecting specific brain regions that control memory and cognitive functions. Epidemiological studies suggest that exercise and dietary antioxidants are beneficial in reducing AD risk. To date, botanical flavonoids are consistently associated with the prevention of age-related diseases. The present study investigated the effects of 4 months of wheel-running exercise, initiated at 2-months of age, in conjunction with the effects of the green tea catechin (-)-epigallocatechin-3-gallate (EGCG) administered orally in the drinking water (50 mg/kg daily) on: (1) behavioral measures: learning and memory performance in the Barnes maze, nest building, open-field, anxiety in the light-dark box; and (2) soluble amyloid-ß (Aß) levels in the cortex and hippocampus in TgCRND8 (Tg) mice. Untreated Tg mice showed hyperactivity, relatively poor nest building behaviors, and deficits in spatial learning in the Barnes maze. Both EGCG and voluntary exercise, separately and in combination, were able to attenuate nest building and Barnes maze performance deficits. Additionally, these interventions lowered soluble Aß1-42 levels in the cortex and hippocampus. These results, together with epidemiological and clinical studies in humans, suggest that dietary polyphenols and exercise may have beneficial effects on brain health and slow the progression of AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/fisiopatologia , Catequina/análogos & derivados , Atividade Motora/fisiologia , Nootrópicos/farmacologia , Administração Oral , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Ansiedade/tratamento farmacológico , Ansiedade/fisiopatologia , Catequina/farmacologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiopatologia , Modelos Animais de Doenças , Água Potável , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Abrigo para Animais , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fragmentos de Peptídeos/metabolismoRESUMO
Indirect modulation of cholinergic activity by cholinesterase inhibition is currently a widely established symptomatic treatment for Alzheimer's disease (AD). Selective activation of certain muscarinic receptor subtypes has emerged as an alternative cholinergic-based amyloid-lowering strategy for AD, as selective muscarinic M1 receptor agonists can reduce amyloid-ß (Aß) production by shifting endoproteolytic amyloid-ß protein precursor (AßPP) processing toward non-amyloidogenic pathways. In this study, we addressed the hypothesis that acute stimulation of muscarinic M1 receptors can inhibit Aß production in awake and freely moving AßPP transgenic mice. By combining intracerebral microdialysis with retrodialysis, we determined hippocampal Aß concentrations during simultaneous pharmacological modulation of brain M1 receptor function. Infusion with a M1 receptor agonist AF102B resulted in a rapid reduction of interstitial fluid (ISF) Aß levels while treatment with the M1 antagonist dicyclomine increased ISF Aß levels reaching significance within 120 minutes of treatment. The reduction in Aß levels was associated with PKCα and ERK activation resulting in increased levels of the α-secretase ADAM17 and a shift in AßPP processing toward the non-amyloidogenic processing pathway. In contrast, treatment with the M1 receptor antagonist dicyclomine caused a decrease in levels of phosphorylated ERK that was independent of PKCα, and led to an elevation of ß-secretase levels associated with increased amyloidogenic AßPP processing. The results of this study demonstrate rapid effects of in vivo M1 receptor modulation on the ISF pool of Aß and suggest that intracerebral microdialysis with retrodialysis is a useful technical approach for monitoring acute treatment effects of muscarinic receptor modulators on AßPP/Aß metabolism.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Hipocampo/metabolismo , Microdiálise/métodos , Receptor Muscarínico M1/metabolismo , Actinas/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Ácido Aspártico Endopeptidases/metabolismo , Diciclomina/farmacologia , Relação Dose-Resposta a Droga , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Hipocampo/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Agonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/farmacologia , Quinuclidinas/farmacologia , Estatísticas não Paramétricas , Tiofenos/farmacologiaRESUMO
Metals such as aluminum, iron, copper, and zinc have been implicated in the etiology of certain neurodegenerative disorders. On the other hand, it is well known that citric acid enhances Al absorption through the diet, while melatonin may bind such metals and decrease ROS production. In this study, we determined the concentrations of Al, Cu, Zn, Fe, and Mn in various tissues of Tg2576 Al-treated mice. Female mice and wild type littermates were exposed to 1mg Al/g plus 3.2% of citric acid and melatonin 10mg/kg/day for 15months. At 18months of age, metal concentrations were measured in bone, liver, kidney and spleen, as well as in three brain regions. In the citric plus Al group, Al levels were higher in hippocampus than in cortex and cerebellum, while Al concentration in bone was higher than those in kidney, liver and spleen, The current results show that exposure to Al plus citric acid did not produce relevant changes in metal levels related with genotype. Moreover, co-administration of melatonin with Al did not modify significantly metal concentrations in tissues. The present results do not support that melatonin can diminish Al or Fe concentrations in various tissues.
Assuntos
Alumínio/farmacocinética , Melatonina/administração & dosagem , Metais Pesados/metabolismo , Administração Oral , Alumínio/administração & dosagem , Animais , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Ácido Cítrico/farmacologia , Cobre/metabolismo , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ferro/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Manganês/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Baço/efeitos dos fármacos , Baço/metabolismo , Zinco/metabolismoRESUMO
The formation and accumulation of toxic amyloid-ß peptides (Aß) in the brain may drive the pathogenesis of Alzheimer's disease. Accordingly, disease-modifying therapies for Alzheimer's disease and related disorders could result from treatments regulating Aß homeostasis. Examples are the inhibition of production, misfolding, and accumulation of Aß or the enhancement of its clearance. Here we show that oral treatment with ACI-91 (Pirenzepine) dose-dependently reduced brain Aß burden in AßPPPS1, hAßPPSL, and AßPP/PS1 transgenic mice. A possible mechanism of action of ACI-91 may occur through selective inhibition of muscarinic acetylcholine receptors (AChR) on endothelial cells of brain microvessels and enhanced Aß peptide clearance across the blood-brain barrier. One month treatment with ACI-91 increased the clearance of intrathecally-injected Aß in plaque-bearing mice. ACI-91 also accelerated the clearance of brain-injected Aß in blood and peripheral tissues by favoring its urinal excretion. A single oral dose of ACI-91 reduced the half-life of interstitial Aß peptide in pre-plaque mhAßPP/PS1d mice. By extending our studies to an in vitro model, we showed that muscarinic AChR inhibition by ACI-91 and Darifenacin augmented the capacity of differentiated endothelial monolayers for active transport of Aß peptide. Finally, ACI-91 was found to consistently affect, in vitro and in vivo, the expression of endothelial cell genes involved in Aß transport across the Blood Brain Brain (BBB). Thus increased Aß clearance through the BBB may contribute to reduced Aß burden and associated phenotypes. Inhibition of muscarinic AChR restricted to the periphery may present a therapeutic advantage as it avoids adverse central cholinergic effects.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Barreira Hematoencefálica/metabolismo , Angiopatia Amiloide Cerebral/metabolismo , Modelos Animais de Doenças , Antagonistas Muscarínicos/uso terapêutico , Fenótipo , Receptores Muscarínicos/metabolismo , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Angiopatia Amiloide Cerebral/tratamento farmacológico , Angiopatia Amiloide Cerebral/patologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Antagonistas Muscarínicos/farmacologia , Pirenzepina/farmacologia , Pirenzepina/uso terapêuticoRESUMO
Olfactory dysfunction is closely related to Alzheimer's disease (AD). Yet the mechanism behind this dysfunction remains largely unknown. To clarify the relationship between olfactory and memory deficits, we assessed behavioral and olfactory system pathology in AßPP/PS1 transgenic mice using the olfactory threshold test, the Morris water maze, Western blotting, immunohistochemistry (IHC), and thioflavine-s staining. Western blotting revealed the following spatial-temporal deposition of amyloid-ß (Aß): appeared in the olfactory epithelium at 1-2 months old (mo); expanded to the olfactory bulb at 3-4 mo; expanded to the anterior olfactory nucleus, piriform cortex, entorhinal cortex, and hippocampus at 6-7 mo; and increased with age (9-10 mo) in the more central cortices. IHC staining showed similar results, but the appearance time points for the spotty signals in these brain regions were earlier due to the higher spatial resolution compared with Western blotting. The spread of Aß deposits from the olfactory epithelium to the olfactory bulb, the anterior olfactory nucleus, and piriform cotex (faint) at 3-4 mo correlated with the olfactory detection deficit found at the corresponding age; and the high level of depositions in the more central regions at 9-10 mo correlated with spatial memory deficit at the same age. We also found that a decline in the levels of olfactory marker protein, a marker of functioning olfactory sensory neuron, coincided with soluble Aß aggregates from a very early age in the olfactory epithelium, indicating early olfactory sensory neuron degeneration in the AßPP/PS1 mouse as in AD patients. The current data suggest that the early deposition of soluble Aß aggregates in the olfactory system and the early deficit in olfactory dysfunction have the potential to serve as molecular markers for the early diagnosis of AD.