Blood-brain barrier dysfunction underlying Alzheimer's disease is induced by an SSAO/VAP-1-dependent cerebrovascular activation with enhanced Aβ deposition
| Autor: | María Esteban-Lopez, Cristina Fábregas, Biel Taltavull, José Rodríguez-Alvarez, Rut Fadó, Alfredo J. Miñano-Molina, Núria Casals, Montse Solé, Mercedes Unzeta |
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| Rok vydání: | 2019 |
| Předmět: |
STAT3 Transcription Factor
0301 basic medicine Amine oxidase Inflammation Disease Pharmacology Blood–brain barrier Endothelial activation Mice 03 medical and health sciences 0302 clinical medicine Alzheimer Disease Cell Adhesion Leukocytes medicine Animals Humans Molecular Biology chemistry.chemical_classification Reactive oxygen species Amyloid beta-Peptides Interleukin-6 Interleukin-8 Brain Endothelial Cells Vascular Endothelial Growth Factor Receptor-2 Coculture Techniques In vitro 030104 developmental biology medicine.anatomical_structure Enzyme chemistry Blood-Brain Barrier Molecular Medicine Amine Oxidase (Copper-Containing) medicine.symptom Cell Adhesion Molecules Neuroglia 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1865:2189-2202 |
| ISSN: | 0925-4439 |
| DOI: | 10.1016/j.bbadis.2019.04.016 |
| Popis: | Dysfunctions of the vascular system directly contribute to the onset and progression of Alzheimer's disease (AD). The blood-brain barrier (BBB) shows signs of malfunction at early stages of the disease. When Abeta peptide (Aβ) is deposited on brain vessels, it induces vascular degeneration by producing reactive oxygen species and promoting inflammation. These molecular processes are also related to an excessive SSAO/VAP-1 (semicarbazide-sensitive amine oxidase) enzymatic activity, observed in plasma and in cerebrovascular tissue of AD patients. We studied the contribution of vascular SSAO/VAP-1 to the BBB dysfunction in AD using in vitro BBB models. Our results show that SSAO/VAP-1 expression is associated to endothelial activation by altering the release of pro-inflammatory and pro-angiogenic angioneurins, most highly IL-6, IL-8 and VEGF. It is also related to a BBB structure alteration, with a decrease in tight-junction proteins such as zona occludens or claudin-5. Moreover, the BBB function reveals increased permeability and leukocyte adhesion in cells expressing SSAO/VAP-1, as well as an enhancement of the vascular Aβ deposition induced by mechanisms both dependent and independent of the enzymatic activity of SSAO/VAP-1. These results reveal an interesting role of vascular SSAO/VAP-1 in BBB dysfunction related to AD progression, opening a new window in the search of alternative therapeutic targets for fighting AD. |
| Databáze: | OpenAIRE |
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