Non-productive angiogenesis disassembles A\xdf plaque-associated blood vessels

María I Álvarez-Vergara ,Nieves Lara-Ureña,Miguel Martin-Bornez,Jakob Körbelin,Pedro Gómez-Gálvez,Ana C Sánchez-Hidalgo ,Martin Trepel,Luis Escudero ,Miriam Echevarrı́a ,Rosana March-Díaz ,Andrea Bullones-Bolaños ,Clara Ortega-De San Luis,R Toro ,Antonia Gutiérrez ,Fernando De Castro,Eloı́sa Herrera ,José Luis Trillo-Contreras ,Alberto Rábano ,Miguel Marchena ,Guiomar Rodríguez-Periñán ,Javier Vitórica ,Pablo Vicente‐Munuera ,Manuel A Sanchez-Garcia,Alicia E Rosales-Nieves,Javier Villadiego,Rocio González-Martínez ,Francisco G Scholl,Beatriz Fernández-Gómez ,José Carlos Dávila ,Alberto Pascual

doi:10.1038/s41467-021-23337-z

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.

Highlights

The human Alzheimer’s disease (AD) brain accumulates angiogenic markers but paradoxically, the cerebral microvasculature is reduced around amyloid ß (Aß) plaques
We combined in situ hybridization (ISH) with immunofluorescence for either the astrocytic marker glial fibrillary acidic protein (GFAP) or the ionized calcium binding adaptor molecule 1 (IBA1) microglial marker, another cell type commonly associated with Aß plaques
To further evaluate the angiogenesis in the AD mouse brain, we studied the expression of the integrin αvß[3] (Iαvß3), a transient marker of angiogenic cells[30] required for the stabilization of VEGFR2 upon binding to VEGF31

Summary

Introduction

The human Alzheimer’s disease (AD) brain accumulates angiogenic markers but paradoxically, the cerebral microvasculature is reduced around Aß plaques. 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. We show that the molecular signature of NPA is highly enriched in AD endothelial cells, abnormal vascular structures accumulate around Aß plaques in two different AD mouse models using histologic NPA markers, and the transcriptional activity of NOTCH is reduced. In mouse models, that adult genetic reduction of lateral inhibition in cerebral endothelial cells is sufficient to produce similar vascular anomalies in the absence of Aß overexpression. These abnormal vascular areas in the brain of AD mouse models replace blood vessels forming vascular scars (VaS). The disassembly of Aß plaque-associated blood vessels involves microglial recruitment and phagocytosis of endothelial cells and, again, induction of NPA is sufficient to induce vessel phagocytosis by microglia in the absence of Aß deposition

Methods

Results

Conclusion