Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
Volume 1865, Issue 9, Pages 2189-2202Publisher
ELSEVIER
DOI: 10.1016/j.bbadis.2019.04.016
Keywords
Alzheimer's disease (AD); Angioneurins; Blood-brain barrier (BBB); Neurovascular unit (NVU); Semicarbazide-sensitive amine oxidase (SSAO/VAP-1)
Funding
- Ministerio de Economia y Competitividad [SAF2014-59697-R, SAF2017-89271-R]
- CIBERNED [CB06/05/0042]
- Fundacio La Marato de TV3 [2014-3610]
- Generalitat de Catalunya [SGR2009-1231, SGR2014-0984]
- Departament de Bioquimica i Biologia Molecular, in UAB
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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 (AD) 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 A beta 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.
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