SSAO/VAP-1 in Cerebrovascular Disorders: A Potential Therapeutic Target for Stroke and Alzheimer’s Disease

Abstract

The semicarbazide-sensitive amine oxidase (SSAO), also known as vascular adhesion protein-1 (VAP-1) or primary amine oxidase (PrAO), is a deaminating enzyme highly expressed in vessels that generates harmful products as a result of its enzymatic activity. As a multifunctional enzyme, it is also involved in inflammation through its ability to bind and promote the transmigration of circulating leukocytes into inflamed tissues. Inflammation is present in different systemic and cerebral diseases, including stroke and Alzheimer’s disease (AD). These pathologies show important affectations on cerebral vessels, together with increased SSAO levels. This review summarizes the main roles of SSAO/VAP-1 in human physiology and pathophysiology and discusses the mechanisms by which it can affect the onset and progression of both stroke and AD. As there is an evident interrelationship between stroke and AD, basically through the vascular system dysfunction, the possibility that SSAO/VAP-1 could be involved in the transition between these two pathologies is suggested. Hence, its inhibition is proposed to be an interesting therapeutical approach to the brain damage induced in these both cerebral pathologies.

Acute high‐altitude hypoxia exposure causes neurological deficits via formaldehyde accumulation

“…However, there was no significant change in the SSAO activity in the brain, which may relate to the location of SSAO and the duration of hypoxia. The activity of SSAO is different in diverse cell types after hypoxia, 32,33 which also shows a time‐dependent mode, as it increased in 6 h and decreased after 24 h hypoxia 11 . Consistently, our cellular experiment showed that the activity of SSAO was gradually increased and peaked at 8 h. In addition, the hypothalamic–pituitary–adrenal (HPA) axis is activated in hypoxic conditions, 34 and then triggered methylamine release and FA formation 35 .…”

Inhibition of vascular adhesion protein 1 protects dopamine neurons from the effects of acute inflammation and restores habit learning in the striatum

“…Our finding that VAP-1 inhibition protected DA neurons from degeneration and rescued behavioural function can be explained as a down-stream effect of an earlier modulation of neutrophil extravasation, as well as a consequence of the inhibition of SSAO enzymatic activity. In fact, VAP-1 is not only an adhesion protein; it also carries an enzymatic moiety that is widely diffused in the blood, with by-products such as ammonia, H 2 O 2 , formaldehyde and methylglyoxal increasing oxidative stress, vascular degeneration and protein unfolding [ 72 – 74 ]. Moreover, H 2 O 2 has been implicated as an underlying factor in the initiation and progression of Parkinson’s disease.…”

Non-coding RNAs in the regulation of blood–brain barrier functions in central nervous system disorders

“…At the cellular level, BBB is formed by brain microvascular endothelial cells (BMECs), astrocytes end-feet and pericytes, and cell-cell adhesion molecules (mainly tight junctions, TJs) tightly seal a monolayer of brain endothelial cells in the capillary microvasculature to form a highly selective diffusion barrier. The diffusion barrier can selectively prevent the passive exchange of solutes and neurotoxic molecules, regulate the trafficking of macromolecules, ions, amino acids, peptides, and signaling molecules, and the entry of leukocytes [ 24 – 27 ] between the blood and the brain [ 23 , 28 ].…”