OVEREXPRESSION OF NOTCH INTRACELLULAR DOMAIN IN BRAIN ENDOTHELIAL CELLS AMELIORATES ALZHEIMER’S DISEASE PROGRESSION

In previous studies, we identified low-perfused vascular abnormalities, termed “vascular scars” (VaS), surrounding Aß plaques in Alzheimer's disease (AD) mouse models. We hypothesized that reduction of the DLL4/NOTCH pathway, a process known as non-productive angiogenesis, in brain endothelial cells (BECs) leads to the accumulation of abnormal vascular cells that are recognized and phagocyted by microglia, leaving behind a VaS. Here we explore the relation between BECs and microglia around Aß plaques in AD mouse models. On the one hand, we evaluate the consequences of microglial activity over BECs by treating 4-month-old AD mice with the microglia inhibitor PLX3397 for two months. Both wild-type and AD mice showed a very efficient microglial removal, with the exception of a residual number of microglia associated to Aß plaques. Although no differences in Aß load were found, PLX treatment significantly increased the proportion of plaques without VaS and accentuated non-productive angiogenesis signature in isolated BECs, suggesting microglial contribution to VaS formation. On the other hand, we develop a viral vector to overcome non-productive angiogenesis in AD mice by expressing NOTCH intracellular domain 1 (NICD1) in BECs. Remarkably, AD mice injected with AAV2-BR1-NICD1 exhibited improved performance in memory tests, indicating partial rescue of pathology-associated cognitive deficits, and increased hippocampal synaptic protein levels. Although NICD1 overexpression doesn’t change Aß nor VaS load, it differentially affects microglial number and load, reducing them in males while increasing them in females. These findings position vascular dysfunction as an important contributor to AD, offering insights into potential therapeutic avenues.