1. Non-productive angiogenesis disassembles Aß plaque-associated blood vessels.
- Author
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Alvarez-Vergara MI, Rosales-Nieves AE, March-Diaz R, Rodriguez-Perinan G, Lara-Ureña N, Ortega-de San Luis C, Sanchez-Garcia MA, Martin-Bornez M, Gómez-Gálvez P, Vicente-Munuera P, Fernandez-Gomez B, Marchena MA, Bullones-Bolanos AS, Davila JC, Gonzalez-Martinez R, Trillo-Contreras JL, Sanchez-Hidalgo AC, Del Toro R, Scholl FG, Herrera E, Trepel M, Körbelin J, Escudero LM, Villadiego J, Echevarria M, de Castro F, Gutierrez A, Rabano A, Vitorica J, and Pascual A
- Subjects
- Alzheimer Disease metabolism, Amyloid beta-Peptides metabolism, Animals, Blood Vessels pathology, Brain blood supply, Brain pathology, Disease Models, Animal, Endothelial Cells metabolism, Female, Gene Expression Profiling methods, Humans, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Neovascularization, Pathologic metabolism, Plaque, Amyloid metabolism, Reverse Transcriptase Polymerase Chain Reaction methods, Mice, Alzheimer Disease genetics, Amyloid beta-Peptides genetics, Blood Vessels metabolism, Brain metabolism, Neovascularization, Pathologic genetics, Plaque, Amyloid genetics
- Abstract
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.
- Published
- 2021
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