Non-productive angiogenesis disassembles Aß plaque-associated blood vessels

• Published in: Nature communications Vol. 12; no. 1; p. 3098
• Main Authors: Alvarez-Vergara, Maria I., Rosales-Nieves, Alicia E., March-Diaz, Rosana, Rodriguez-Perinan, Guiomar, Lara-Ureña, Nieves, Ortega-de San Luis, Clara, Sanchez-Garcia, Manuel A., Martin-Bornez, Miguel, Gómez-Gálvez, Pedro, Vicente-Munuera, Pablo, Fernandez-Gomez, Beatriz, Marchena, Miguel A., Bullones-Bolanos, Andrea S., Davila, Jose C., Gonzalez-Martinez, Rocio, Trillo-Contreras, Jose L., Sanchez-Hidalgo, Ana C., del Toro, Raquel, Scholl, Francisco G., Herrera, Eloisa, Trepel, Martin, Körbelin, Jakob, Escudero, Luis M., Villadiego, Javier, Echevarria, Miriam, de Castro, Fernando, Gutierrez, Antonia, Rabano, Alberto, Vitorica, Javier, Pascual, Alberto
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.05.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/31; 13/51; 13/95; 14/19; 14/28; 14/32; 38/61; 631/378/1689/1283; 631/378/340; 64/60; 692/617/375/1370; 96/35; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Angiogenesis; Animal models; Animals; Anomalies; Blood vessels; Blood Vessels - metabolism; Blood Vessels - pathology; Brain - blood supply; Brain - metabolism; Brain - pathology; Disease Models, Animal; Dismantling; Endothelial cells; Endothelial Cells - metabolism; Female; Gene Expression Profiling - methods; Humanities and Social Sciences; Humans; Markers; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microglia; Microvasculature; multidisciplinary; Mutation; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Neurodegenerative diseases; Phagocytosis; Phenotypes; Plaque, Amyloid - genetics; Plaque, Amyloid - metabolism; Plaques; Presenilin; Reverse Transcriptase Polymerase Chain Reaction - methods; Scars; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23337-z

The human Alzheimer’s disease (AD) brain accumulates angiogenic markers but paradoxically, the cerebral microvasculature is reduced around Aß plaques. Here we demonstrate that angiogenesis is started near Aß plaques in both AD mouse models and human AD samples. However, endothelial cells express the molecular signature of non-productive angiogenesis (NPA) and accumulate, around Aß plaques, a tip cell marker and IB4 reactive vascular anomalies with reduced NOTCH activity. Notably, NPA induction by endothelial loss of presenilin, whose mutations cause familial AD and which activity has been shown to decrease with age, produced a similar vascular phenotype in the absence of Aß pathology. We also show that Aß plaque-associated NPA locally disassembles blood vessels, leaving behind vascular scars, and that microglial phagocytosis contributes to the local loss of endothelial cells. These results define the role of NPA and microglia in local blood vessel disassembly and highlight the vascular component of presenilin loss of function in AD. Aß are extracellular deposits relevant in Alzheimer’s disease (AD). This study shows that Aß plaques are hubs of endothelial disassembly that induce non-productive angiogenesis. This process is aided by the microglia and unchained by reduced presenilin function, a trait of AD, in endothelial cells.