Beta secretase 1-dependent amyloid precursor protein processing promotes excessive vascular sprouting through NOTCH3 signaling

Change log
Durrant, Claire S 
Ruscher, Karsten 
Özen, Ilknur 

Amyloid beta peptides (Aβ) proteins play a key role in vascular pathology in Alzheimer’s Disease (AD) including impairment of the blood brain barrier and aberrant angiogenesis. Although previous work has demonstrated a pro-angiogenic role of Aβ, the exact mechanisms by which amyloid precursor protein (APP) processing and endothelial angiogenic signalling cascades interact in AD remain a largely unsolved problem. Here, we report that increased endothelial sprouting in human-APP transgenic mouse (TgCRND8) tissue is dependent on β-secretase (BACE1) processing of APP. Higher levels of Aβ processing in TgCRND8 tissue coincides with decreased NOTCH3/JAG1 signalling, over-production of endothelial filopodia and increased numbers of vascular pericytes. Using a novel in vitro approach to study sprouting angiogenesis in TgCRND8 organotypic brain slice cultures (OBSCs), we find that BACE1 inhibition normalises excessive endothelial filopodia formation and restores NOTCH3 signalling. These data present the first evidence for the potential of BACE1 inhibition as an effective therapeutic target for aberrant angiogenesis in AD.

Amyloid Precursor Protein Secretases, Amyloid beta-Protein Precursor, Animals, Aspartic Acid Endopeptidases, Cerebral Cortex, Endothelial Cells, Enzyme Inhibitors, Female, In Vitro Techniques, Jagged-1 Protein, Male, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Transgenic, Microvascular Density, Neovascularization, Pathologic, Pseudopodia, Receptor, Notch3, Signal Transduction
Journal Title
Cell Death and Disease
Conference Name
Journal ISSN
Volume Title
Nature Publishing Group
This work was funded by Alzheimer's Research UK project grant ARUK-PG2015-24, the John and Lucille Van Geest Foundation, Swedish Brain Fund (FO2019-0254; FO218-0316), the Hans-Gabriel and Alice Trolle-Wachtmeister Foundation and Sparbanksstiftelsen Fars & Frosta.