Blood-brain barrier dysfunction underlying Alzheimer's disease is induced by an SSAO/VAP-1-dependent cerebrovascular activation with enhanced Aβ deposition

May 4, 2019Biochimica et biophysica acta. Molecular basis of disease

Blood vessel activation linked to a specific enzyme may cause blood-brain barrier problems and increased amyloid buildup in Alzheimer's disease

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Abstract

SSAO/VAP-1 expression is associated with endothelial activation and BBB dysfunction in Alzheimer's disease.

Endothelial activation is linked to altered release of pro-inflammatory and pro-angiogenic factors, notably IL-6, IL-8, and VEGF.
There is a decrease in tight-junction proteins, such as zona occludens and claudin-5, indicating structural changes in the BBB.
Increased permeability and leukocyte adhesion are observed in cells expressing SSAO/VAP-1.
Vascular Aβ deposition is enhanced by mechanisms that are both dependent and independent of SSAO/VAP-1 enzymatic activity.

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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 (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.

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Blood-brain barrier dysfunction underlying Alzheimer's disease is induced by an SSAO/VAP-1-dependent cerebrovascular activation with enhanced Aβ deposition

Abstract

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