Role of SSAO/VAP-1 expression on the effect of soluble amyloid-beta forms on synapses in a neurovascular environment

Abstract

Alzheimer’s disease (AD) is rapidly becoming one of the most lethal, expensive and burdening diseases of this century representing up to 60 – 70 % of dementia cases. During many years, multiple drugs developed to treat this pathology have been designed assuming that amyloid β-peptide (Aβ) drives the disease. However, this approach has not yielded therapeutics that cure or produce significant improvements. In this regard, a broader outlook considering alternative mechanisms driving AD may be required. Different kinds of dementia, including AD, are related with several risk factors such as pathological vascular alterations (i.e. diabetes, atherosclerosis and malignant hypertension) and disturbances in brain microcirculation (i.e. defective blood-brain barrier functions and breakdown). This relationship evidences an intercellular communication between the cerebrovasculature and neurons, which is mainly mediated by multiple messenger molecules known as angioneurins. To study this interrelation and the role of these signaling factors, we decided to focus on the neurovascular unit (NVU) and we established a new in vitro system constituted by microvascular endothelial cells, neurons and astrocytes. We took advantage of the human cerebral microvascular endothelial cell line (hCMEC/D3) expressing the human semicarbazide-sensitive amine oxidase, also known as vascular adhesion protein-1 (hSSAO/VAP-1) as a model of vascular alteration in AD. hSSAO/VAP-1 was described to be increased in plasma and cerebrovascular tissue from AD patients. Analyzing endothelial-secreted angioneurins in these cells we observed that hSSAO/VAP-1 expression induced an activity-independent significant decrease in its brain-derived neurotrophic factor (BDNF) releasing levels. Assessing the impact of such BDNF reduction on neurons we found that, co-culturing with hSSAO/VAP-1 endothelial cells in a context mimicking Aβ pathological presence induced a decrease of PSD95 and GluA1 synaptic protein levels. Moreover, we determined the relevance of having the appropriate endothelial-secreted BDNF levels for neuronal network maintenance. In summary, our results revealed for the first time that hSSAO/VAP-1 enzyme alters endothelial BDNF secretion and that this neurotrophin is a critical mediator between endothelial cells and neurons within our NVU in vitro system. In fact our results suggest that hSSAO/VAP-1 induces a sensitization, due to endothelial-secreted BDNF reduction, of co-cultured neurons to face an aversive stimulus such as Aβ. On one hand, BDNF is a key factor involved in AD pathology as its depletion has been associated with the main pathological hallmarks of the disease. On the other hand, the hSSAO/VAP-1 is increased in several systemic vascular pathologies, also considered risk factors for AD. Therefore, although more experiments are required, we suggest that designing a potential therapeutic strategy based on BDNF and/or decreasing the hSSAO/VAP-1 expression may result extremely powerful.

Date of Award	21 Jul 2022
Original language	English
Supervisor	Alfredo Jesús Miñano Molina (Director), Jose Rodriguez Alvarez (Director) & Montse Solé (Director)