RESUMO
The blood-brain barrier consists of a tightly sealed monolayer of endothelial cells being vital in maintaining a stable intracerebral microenvironment. The barrier is receptive to leakage upon exposure to environmental factors, like hypoxia, and its disruption has been suggested as a constituent in the pathophysiology of both neurological and psychiatric disorders. The schizophrenia associated ZEB1 gene encodes a transcription factor susceptible to transcriptional control by a hypoxia induced factor, HIF1A, known to be implicated in blood-brain barrier dysfunction. However, whether ZEB1 is also implicated in maintaining blood-brain barrier integrity upon hypoxia is unknown. Here we assessed Hif1a, Zo1 and Zeb1 mRNA expression and ZO1 protein abundancy in a mimetic system of the in vivo blood-brain barrier comprising mouse brain endothelial cells subjected to the norm- and proven hypoxic conditions. Despite that, Hif1a mRNA expression was significantly increased, clearly indicating that the oxygen-deprived environment introduced a hypoxia response in the cells, we found no hypoxia-induced changes in neither ZO1 abundancy nor in the expression of Zo1 and Zeb1 mRNA. However, independent of hypoxia status, we found that Zeb1 and Zo1 mRNA expression is highly correlated. Further studies are warranted that investigate the implication of the ZEB1/ZO1 axis in blood-brain barrier maintenance under different physiological conditions.
Assuntos
Barreira Hematoencefálica/metabolismo , Microambiente Celular , Células Endoteliais/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Animais , Hipóxia Celular , Linhagem Celular , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regulação para Cima , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Proteína da Zônula de Oclusão-1/genética , Proteína da Zônula de Oclusão-1/metabolismoRESUMO
To enhance early diagnosis and treatment of Alzheimer·s disease (AD), understanding the pathological changes before symptoms arise is crucial. The continuum model of AD suggest that Aß beta (Aß) accumulation precedes symptoms by at least 15 years, with vascular changes detectable around this time. Disturbances in capillary flow dynamics have been linked to reduced oxygen delivery to brain tissue, but evidence in presymptomatic AD remains elusive. We examined capillary flow dynamics in presymptomatic Tg-SwDI mice and the capacity of carbonic anhydrase inhibitors (CAIs) to prevent capillary flow disturbances. Our study revealed capillary flow disturbances associated with alterations in capillary morphology, adhesion molecule expression, and Aß load in cognitively normal 9-10-month-old Tg-SwDI mice. Treated mice showed ameliorated capillary flow disturbances, enhanced oxygen availability, and reduced Aß load. These findings underscore the importance of capillary flow disturbances in presymptomatic AD and highlight CAIs· potential for preserving vascular integrity in early AD.