SSAO-mediated decrease of endothelial BDNF release affects neuronal GluA1 and PSD95 expression: a peripheral mechanism inducing NVU and CNS disturbances

Abstract

Dysfunction of the vascular system contributes to brain damage and neurodegeneration, and cerebral amyloid angiopathy (CAA) can be identified in a high percentage of Alzheimer disease (AD) brains. Blood-brain barrier (BBB) alterations can affect communication and signalling between neurovascular unit (NVU) components through changes in the release of angioneurins, among others. The two-hit vascular hypothesis of AD suggests that chronic vascular risk factors cause an early damage to the brain microvasculature (hit 1) triggering a cascade of events that leads to amyloid β-peptide (Aβ) accumulation in the brain and precipitating the Aβ-dependent pathway of neurodegeneration (hit 2). The vascular enzyme and adhesion molecule SSAO/VAP-1 plays an important role in cerebrovascular dysfunction and vascular Aβ aggregation, acting as an active player in the first of the two-hits. We generated a new NVU in vitro model to study the role of SSAO/VAP-1 on the BBB dysfunction and its effects on neurons in an AD context. We focused on the release of key angioneurins for synaptic plasticity and neuronal survival, highly compromised in AD. Our results show that SSAO/VAP-1 expression, together with the addition of Aβ1-40peptide containing the Dutch mutation (used to mimic CAA condition; AβD), to cerebral endothelial cells synergistically alter the release of vascular BDNF. This alteration subsequently affects the expression of synaptic markers PSD95 and GluA1 in cortical neurons. Moreover, GluA1 and PSD95-positive neurons present reduced immunolabeling intensity of these markers when low levels of vascular BDNF are present. These results reveal vascular BDNF as a possible key element in the sensitization to Aβ due to SSAO/VAP-1 expression, impacting negatively on glutamatergic synaptic and NVU function.HighlightsSSAO/VAP-1 expression alters BBB decreasing ZO-1, VE-Cadherin and Claudin-5 levels.SSAO/VAP-1 expression alters the release of vascular angioneurin BDNF.SSAO/VAP-1 and AβD decrease synaptic protein levels affecting glutamatergic neurons.Endothelial BDNF decrease induced by SSAO/VAP-1 and AβD alters glutamatergic neurons.