RT Journal Article
T1 Non-productive angiogenesis disassembles Aß plaque-associated blood vessels
A1 Alvarez-Vergara, Maria I.
A1 Rosales-Nieves, Alicia E.
A1 March-Diaz, Rosana
A1 Rodriguez-Perinan, Guiomar
A1 Lara-Ureña, Nieves
A1 Ortega-de San Luis, Clara
A1 Sanchez-Garcia, Manuel A.
A1 Martin-Bornez, Miguel
A1 Gómez-Gálvez, Pedro
A1 Vicente-Munuera, Pablo
A1 Fernandez-Gomez, Beatriz
A1 Marchena, Miguel A.
A1 Bullones-Bolanos, Andrea S.
A1 Davila, Jose C.
A1 Gonzalez-Martinez, Rocio
A1 Trillo-Contreras, Jose L.
A1 Sanchez-Hidalgo, Ana C.
A1 del Toro, Raquel
A1 Scholl, Francisco G.
A1 Herrera, Eloisa
A1 Trepel, Martin
A1 Körbelin, Jakob
A1 Escudero, Luis M.
A1 Villadiego, Javier
A1 Echevarria, Miriam
A1 de Castro, Fernando
A1 Gutierrez, Antonia
A1 Rabano, Alberto
A1 Vitorica, Javier
A1 Pascual, Alberto
K1 Alzheimer disease
K1 Brain
K1 Endothelial cells
K1 Presenilins
K1 Péptidos beta-Amiloides
K1 Plaque, amyloid
K1 Blood vessels
K1 Vascular malformations
K1 Angiogenesis
K1 Enfermedad de Alzheimer
K1 Encéfalo
K1 Células endoteliales
K1 Presenilinas
K1 Péptidos beta-amiloides
K1 Placa amiloide
K1 Vasos sanguíneos
K1 Malformaciones vasculares
AB 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.
PB Springer Nature
YR 2021
FD 2021-05-25
LK http://hdl.handle.net/10668/4516
UL http://hdl.handle.net/10668/4516
LA en
NO Alvarez-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):3098
NO A.E.R.-N. was the recipient of a JdlC-F fellowship from the Spanish Ministry of Economy, Industry, and Competitiveness (MINEICO) (FJCI-2015-23708), M.I.A.-V., N.L.-U., and C.O.-d.S.L. were the recipient of an FPU fellowship from Spanish Ministry of Education, Culture, and Sport (respectively, FPU15/02898, FPU14-02115, and AP2010‐1598), and R.M.-D. was the recipient of a “Sara Borrell” fellowship from ISCIII (CD09/0007). Work was supported by grants to A.P. by the Spanish MINEICO, ISCIII, and FEDER (SAF2012‐33816, SAF2015‐64111‐R, RTI2018-096629-B-100, SAF2017-90794-REDT, and PIE13/0004), by the regional Government of Andalusia (“Proyectos de Excelencia”, P12‐CTS‐2138 and P12‐CTS‐2232) co-funded by CEC and FEDER funds, and by the “Ayuda de Biomedicina 2018”, Fundación Domingo Martínez; J.Vitorica: Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union (PI18/01556) by La Marató-TV3 Foundation grant 20141431; by CIBERNED (CB06/05/0094); and by Junta de Andalucia Consejería de Economía y Conocimiento through grant US-1262734; A.G.: Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union, through grant PI18/01557; and by Junta de Andalucia Consejería de Economía y Conocimiento through grants UMA18-FEDERJA-211 and P18-RT-2233 co-financed by Programa Operativo FEDER 2014-2020. The authors thank Maria Llorens-Martin (CBM-Severo Ochoa, Madrid, Spain) for the generous gift of the human samples; Ralf H. Adams and Jose L. de la Pompa for providing the Cdh5-Cre::ERT2 and Cp-HIST1H2BB::Venus mice; K. Levitsky (microscopy), M.J. Castro (flow cytometry), F.J. Moron (genomics), and R. Duran (histology) for advice and technical assistance in experiments at IBiS core facilities and to Dr. Alberto Serrano-Pozo for his critical review of the manuscript. We thank Sanofi (France) for the APP751SL model used in this work.
DS RISalud
RD Apr 10, 2025