RESUMO
Amyloid-beta peptide (Abeta) interacts with the vasculature to influence Abeta levels in the brain and cerebral blood flow, providing a means of amplifying the Abeta-induced cellular stress underlying neuronal dysfunction and dementia. Systemic Abeta infusion and studies in genetically manipulated mice show that Abeta interaction with receptor for advanced glycation end products (RAGE)-bearing cells in the vessel wall results in transport of Abeta across the blood-brain barrier (BBB) and expression of proinflammatory cytokines and endothelin-1 (ET-1), the latter mediating Abeta-induced vasoconstriction. Inhibition of RAGE-ligand interaction suppresses accumulation of Abeta in brain parenchyma in a mouse transgenic model. These findings suggest that vascular RAGE is a target for inhibiting pathogenic consequences of Abeta-vascular interactions, including development of cerebral amyloidosis.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Barreira Hematoencefálica/fisiologia , Encéfalo/metabolismo , Receptores Imunológicos/metabolismo , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/farmacologia , Animais , Encéfalo/irrigação sanguínea , Circulação Cerebrovascular , Citocinas/genética , Citocinas/metabolismo , Antagonistas dos Receptores de Endotelina , Endotelina-1/efeitos dos fármacos , Endotelina-1/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Oligopeptídeos/farmacologia , Fragmentos de Peptídeos/farmacologia , Transporte Proteico/fisiologia , Receptor para Produtos Finais de Glicação Avançada , Receptor de Endotelina ARESUMO
LRP (low-density lipoprotein receptor-related protein) is linked to Alzheimer's disease (AD). Here, we report amyloid beta-peptide Abeta40 binds to immobilized LRP clusters II and IV with high affinity (Kd = 0.6-1.2 nM) compared to Abeta42 and mutant Abeta, and LRP-mediated Abeta brain capillary binding, endocytosis, and transcytosis across the mouse blood-brain barrier are substantially reduced by the high beta sheet content in Abeta and deletion of the receptor-associated protein gene. Despite low Abeta production in the brain, transgenic mice expressing low LRP-clearance mutant Abeta develop robust Abeta cerebral accumulations much earlier than Tg-2576 Abeta-overproducing mice. While Abeta does not affect LRP internalization and synthesis, it promotes proteasome-dependent LRP degradation in endothelium at concentrations > 1 microM, consistent with reduced brain capillary LRP levels in Abeta-accumulating transgenic mice, AD, and patients with cerebrovascular beta-amyloidosis. Thus, low-affinity LRP/Abeta interaction and/or Abeta-induced LRP loss at the BBB mediate brain accumulation of neurotoxic Abeta.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Proteínas Relacionadas a Receptor de LDL/metabolismo , Fragmentos de Peptídeos/metabolismo , Peptídeos beta-Amiloides/genética , Animais , Barreira Hematoencefálica/metabolismo , Linhagem Celular , Cricetinae , Humanos , Proteínas Relacionadas a Receptor de LDL/deficiência , Proteínas Relacionadas a Receptor de LDL/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fragmentos de Peptídeos/genética , Ligação Proteica , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismoRESUMO
The complications of diabetes are myriad and represent a rising cause of morbidity and mortality, particularly in the Western world. The update of the Diabetes Control and Clinical Trials Group/Epidemiology of Diabetes Interventions and Complications Research Group (DCCT/EDIC) suggested that previous strict control of hyperglycaemia was associated with reduced carotid atherosclerosis compared to conventional treatment, even after levels of glycosylated haemoglobin between the two treatment groups became indistinguishable. These intriguing findings prompt the key question, why does the blood vessel 'remember'? This review focuses on the hypothesis that the ligand/RAGE axis contributes importantly to glycaemic 'memory'. Studies in rodent models of diabetes suggest that blockade or genetic modification of RAGE suppress diabetes-associated progression of atherosclerosis, exaggerated neointimal expansion consequent to acute arterial injury, and cardiac dysfunction. We propose that therapeutic RAGE blockade will intercept maladaptive diabetes-associated memory in the vessel wall and provide cardiovascular protection in diabetes.
Assuntos
Aterosclerose/metabolismo , Complicações do Diabetes/metabolismo , Angiopatias Diabéticas/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Receptores Imunológicos/metabolismo , Animais , Artérias/metabolismo , Artérias/patologia , Aterosclerose/patologia , Antígenos CD18/metabolismo , Complicações do Diabetes/imunologia , Complicações do Diabetes/patologia , Angiopatias Diabéticas/patologia , Modelos Animais de Doenças , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Glucose/metabolismo , Proteína HMGB1/metabolismo , Humanos , Hiperglicemia/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Complexo Antígeno L1 Leucocitário/imunologia , Complexo Antígeno L1 Leucocitário/metabolismo , Ligantes , Miocárdio/metabolismo , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/genética , Transdução de SinaisRESUMO
The interaction of glucose-modified and inflammation-promoting ligands with the receptor for advanced glycation end products (RAGE) is emerging as a central mechanism contributing to the diverse complications of diabetes. These ligands, particularly in oligomeric form, bind to RAGE and transduce intracellular signals. The consequences of this interaction, as elucidated in cultured cells and animal models, include upregulation of inflammatory and tissue-degradative pathways. Pharmacologic antagonism of RAGE may hold promise for the treatment of diabetic complications.