In previous studies, we identified low-perfused vascular abnormalities, termed “vascular scars”, surrounding A-beta plaques in Alzheimer's disease mouse models. We hypothesized that these vascular scars result from non-productive angiogenesis, a process in which total or partial reduction of the DLL4/NOTCH pathway leads to erratic angiogenesis and disassembly of vessels into non-conducting structures1. In this study, our objective was to investigate whether restoring the NOTCH pathway in brain endothelial cells could enhance vessel stability around A-beta plaques. To this aim, we injected the adeno-associated viral vector AAV2-BR1 in the tail vein of 5-month-old wild type and APP751SL/+ mice. This vector targets brain endothelial cells and delivered either Tomato (control) or NOTCH intracellular domain 1 (NICD1), a key transcription factor in the DLL4/NOTCH pathway. After two months, we performed histological and biochemical analyses on the collected brains. Quantitative RT-PCR confirmed the specific expression of NICD1 in AAV2-BR1-NICD1 mice compared to AAV2-BR1-Tomato mice. Immunofluorescence imaging revealed an increased presence of vascular markers near Aβ plaques in APP751SL/+ mice expressing NICD1. Remarkably, these APP-NICD1 mice exhibited improved performance in the novel object recognition test, indicating a potential rescue of pathology-associated memory deficits. To further elucidate the consequences of NOTCH pathway activation on vessel stability, we are now refining a capillary isolation technique. Our findings position NOTCH pathway activation as a promising approach for ameliorating vascular abnormalities associated with Alzheimer's disease, offering insights into potential therapeutic avenues.1Alvarez-Vergara, M. I. et al. Non-productive angiogenesis disassembles Aß plaque-associated blood vessels. Nat. Commun. 12, 3098 (2021).