期刊
NEUROSCIENCE
卷 440, 期 -, 页码 48-55出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuroscience.2020.05.024
关键词
Alzheimer's disease; blood-brain barrier; tight junctions; amyloid beta (A beta); A beta transporters; permeability
Alzheimer's disease (AD) pathology is characterized by amyloid plaques containing amyloid beta (A beta) peptides, neurofibrillary tangles containing hyperphosphorylated tau protein, and neuronal loss. In addition, A beta deposition in brain microvessels, known as cerebral amyloid angiopathy (CAA), increases blood-brain barrier (BBB) permeability and induces vascular dysfunction which aggravates AD pathology. The aim of the present study was to characterize neurovascular dysfunction in the Tg-SwDI mouse model of AD. Isolated brain capillaries from wild type (WT) and Tg-SwDI mice were used to evaluate the expression of monomeric and aggregated forms of A beta, P-glycoprotein (P-gp), the receptor for advance glycation end-products (RAGE) and the tight junction (TJs) proteins occludin and claudin-5. Cultured brain endothelial cells were used to analyze barrier function via fluorescein flux. Isolated capillaries from Tg-SwDI mice contained increased levels of aggregated and oligomeric A beta compared to WT animals. Isolated capillaries from Tg-SwDI had decreased levels of P-gp, which transports A beta from brain to blood, and increased levels of RAGE, which transports A beta from blood to brain. In addition, the TJ protein occludin was decreased in Tg-SwDI mice relative to WT mice, which correlated with an increase in BBB permeability in cultured brain endothelial cells. These findings demonstrated that Tg-SwDI mice exhibit A beta aggregation that is due, in part, to impaired A beta clearance driven by both a decrease in P-gp and increase in RAGE protein levels in brain capillaries. A beta aggregation promotes a decrease in the expression of the TJ protein occludin, and as consequence an increase in BBB permeability.
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