SSAO-MEDIATED DECREASE OF ENDOTHELIAL BDNF RELEASE AFFECTS NEURONAL GLUA1 AND PSD95 EXPRESSION: A PERIPHERAL MECHANISM INDUCING NVU AND CNS DISTURBANCES

Dysfunction of the vascular system contributes to brain damage and neurodegeneration, and cerebral amyloid angiopathy (CAA) is present in a high percentage of Alzheimer disease (AD) brains. Blood–brain barrier (BBB) alterations can disrupt communication and signalling between neurovascular unit (NVU) components through changes in the release of angioneurins. The two-hit vascular hypothesis of AD proposes that chronic vascular risk factors cause early damage to the brain microvasculature (hit 1), triggering a cascade of events that promotes amyloid β-peptide (Aβ) accumulation and precipitates Aβ-dependent neurodegeneration (hit 2). The vascular enzyme and adhesion molecule SSAO/VAP-1 plays a key role in cerebrovascular dysfunction and vascular Aβ aggregation, acting as an active contributor to the first hit. We generated a novel in vitro NVU model to investigate the role of SSAO/VAP-1 in BBB dysfunction and its effects on neurons in an AD context. We focused on the release of angioneurins involved in synaptic plasticity and neuronal survival, which are severely compromised in AD. Our results show that SSAO/VAP-1 expression, together with the addition of the Aβ1-40 peptide carrying the Dutch mutation (used to mimic CAA conditions; AβD), in cerebral endothelial cells synergistically alters the release of vascular BDNF. This alteration subsequently affects the expression of the synaptic markers PSD95 and GluA1 in cortical neurons. Moreover, GluA1- and PSD95-positive neurons display reduced immunolabeling intensity when exposed to low levels of vascular BDNF. These findings identify vascular BDNF as a key mediator of SSAO/VAP-1-dependent sensitization to Aβ, negatively impacting glutamatergic synaptic function and NVU integrity.