Alvarez-Vergara, Maria I.Rosales-Nieves, Alicia E.March-Diaz, RosanaRodriguez-Perinan, GuiomarLara-Ureña, NievesOrtega-de San Luis, ClaraSanchez-Garcia, Manuel A.Martin-Bornez, MiguelGómez-Gálvez, PedroVicente-Munuera, PabloFernandez-Gomez, BeatrizMarchena, Miguel A.Bullones-Bolanos, Andrea S.Davila, Jose C.Gonzalez-Martinez, RocioTrillo-Contreras, Jose L.Sanchez-Hidalgo, Ana C.del Toro, RaquelScholl, Francisco G.Herrera, EloisaTrepel, MartinKörbelin, JakobEscudero, Luis M.Villadiego, JavierEchevarria, Miriamde Castro, FernandoGutierrez, AntoniaRabano, AlbertoVitorica, JavierPascual, Alberto2022-12-152022-12-152021-05-25Alvarez-Vergara MI, Rosales-Nieves AE, March-Diaz R, Rodriguez-Perinan G, Lara-Ureña N, Ortega-de San Luis C, et al. Non-productive angiogenesis disassembles Aß plaque-associated blood vessels. Nat Commun. 2021 May 25;12(1):3098http://hdl.handle.net/10668/4516The 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.enAtribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/Alzheimer diseaseBrainEndothelial cellsPresenilinsPéptidos beta-AmiloidesPlaque, amyloidBlood vesselsVascular malformationsAngiogenesisEnfermedad de AlzheimerEncéfaloCélulas endotelialesPresenilinasPéptidos beta-amiloidesPlaca amiloideVasos sanguíneosMalformaciones vascularesMedical Subject Headings::Diseases::Nervous System Diseases::Neurodegenerative Diseases::Tauopathies::Alzheimer DiseaseMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Amyloid beta-PeptidesMedical Subject Headings::Organisms::Eukaryota::AnimalsMedical Subject Headings::Anatomy::Cardiovascular System::Blood VesselsMedical Subject Headings::Anatomy::Nervous System::Central Nervous System::BrainMedical Subject Headings::Diseases::Animal Diseases::Disease Models, AnimalMedical Subject Headings::Anatomy::Cells::Epithelial Cells::Endothelial CellsMedical Subject Headings::Check Tags::FemaleMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Gene Expression ProfilingMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, Inbred Strains::Mice, Inbred C57BLMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, Mutant Strains::Mice, KnockoutMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, TransgenicMedical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Metaplasia::Neovascularization, PathologicMedical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Pathological Conditions, Anatomical::Plaque, AmyloidMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Nucleic Acid Amplification Techniques::Polymerase Chain Reaction::Reverse Transcriptase Polymerase Chain ReactionMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::PresenilinsMedical Subject Headings::Anatomy::Cardiovascular System::Blood Vessels::MicrovesselsMedical Subject Headings::Diseases::Skin and Connective Tissue Diseases::Skin Diseases::Skin Abnormalitiesresearch article34035282open access10.1038/s41467-021-23337-z2041-1723PMC8149638