Ubiquitine ligase Pdzrn3 deficiency in endothelium protects against neurodegeneration in a hypoperfusion-induced vascular cognitive impairment and Dementia mouse model

Up to 45% of all dementias worldwide are wholly or partly due to age-related cerebral small vessel disease (SVD) but the pathogenesis of cerebral SVD remains unclear. CNS vascularization possess unique structural properties enabling their organization in the form of blood-brain barrier (BBB). After loss of integrity of the BBB, leakage along vascular tubes and sub-sequent edema can initiate pathogenesis of neurodegenerative diseases. Despite the prevalence of the disease, a clear understanding of the underlying mechanism is still needed. “Wnt signalling” is among the most prominent up-regulated pathway in brain endothelial cells (EC). Building upon our findings showing the regulatory role of an E3 ubiquitin-ligase called PDZRN3, a core component of the Wnt pathway; on BBB integrity, we want here to provide insights into the BBB permeability contribution to brain tissue injury and cognitive impairments. We have set up a mouse model of chronic cerebral hypoperfusion by applying bilateral common carotid artery stenosis to generate a progressive and continuous cerebral blood flow reduction over 28 days. We then challenged mutant mice exhibiting Pdzrn3 either loss or gain of function in EC (iEC-KO and iEC-OE) to manipulate specifically the BBB junctional properties. We report that learning and memory performance is significantly impaired at day 6 in the hypoperfused littermate group when the Pdzrn3 iEC-KO mice show preserved cognitive capacities until day 12. Importantly, Pdzrn3 iEC-KO mice exhibit a significant decrease of brain lesions (microinfarcts) and hippocampal neuronal loss compared to control littermates. Conversely, Pdzrn3 iEC-OE worsened vascular injury with increased BBB leakage compared to control littermates. This work demonstrates a strong relationship between hypoperfusion and the early onset of SVD on one hand and suggests a key role of BBB permeability in the induction of neuronal damage on the other hand.