Non-productive angiogenesis disassembles Aß plaque-associated blood vessels

Maria I. Alvarez-Vergara, Alicia E. Rosales-Nieves, Rosana March-Diaz, Guiomar Rodriguez-Perinan, Nieves Lara-Ureña, Clara Ortega- de San Luis, Manuel A. Sanchez-Garcia, Miguel Martin-Bornez, Pedro Gómez-Gálvez, Pablo Vicente-Munuera, Beatriz Fernandez-Gomez, Miguel A. Marchena, Andrea S. Bullones-Bolanos, Jose C. Davila, Rocio Gonzalez-Martinez, Jose L. Trillo-Contreras, Ana C. Sanchez-Hidalgo, Raquel Toro, Francisco G. Scholl, Eloisa Herrera, Martin Trepel, Jakob Körbelin, Luis M. Escudero, Javier Villadiego, Miriam Echevarria, Fernando Castro, Antonia Gutierrez, Alberto Rabano, Javier Vitorica and Alberto Pascual ()
Additional contact information
Maria I. Alvarez-Vergara: Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla
Alicia E. Rosales-Nieves: Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla
Rosana March-Diaz: Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla
Guiomar Rodriguez-Perinan: Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla
Nieves Lara-Ureña: Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla
Clara Ortega- de San Luis: Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla
Manuel A. Sanchez-Garcia: Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla
Miguel Martin-Bornez: Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla
Pedro Gómez-Gálvez: Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla
Pablo Vicente-Munuera: Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla
Beatriz Fernandez-Gomez: Grupo de Neurobiología del Desarrollo-GNDe, Instituto Cajal-CSIC
Miguel A. Marchena: Grupo de Neurobiología del Desarrollo-GNDe, Instituto Cajal-CSIC
Andrea S. Bullones-Bolanos: Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla
Jose C. Davila: Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)
Rocio Gonzalez-Martinez: Consejo Superior de Investigaciones Científicas-Universidad Miguel Hernández (CSIC-UMH)
Jose L. Trillo-Contreras: Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla
Ana C. Sanchez-Hidalgo: Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla
Raquel Toro: Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla
Francisco G. Scholl: Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla
Eloisa Herrera: Consejo Superior de Investigaciones Científicas-Universidad Miguel Hernández (CSIC-UMH)
Martin Trepel: Department of Hematology and Oncology
Jakob Körbelin: University Medical Center Hamburg-Eppendorf
Luis M. Escudero: Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla
Javier Villadiego: Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla
Miriam Echevarria: Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla
Fernando Castro: Grupo de Neurobiología del Desarrollo-GNDe, Instituto Cajal-CSIC
Antonia Gutierrez: Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)
Alberto Rabano: Fundacion CIEN
Javier Vitorica: Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla
Alberto Pascual: Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23337-z

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