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Cell Death Dis. 2020 Feb 6;11(2):98. doi: 10.1038/s41419-020-2288-4.

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

Author information

1
John van Geest Centre for Brain Repair, Forvie Site, Robinson Way, Cambridge, CB2 0PY, UK.
2
The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK.
3
Centre for Discovery Brain Sciences, University of Edinburgh, 1 George Square, Edinburgh, EH8 9JZ, UK.
4
Laboratory for Experimental Brain Research, Department of Clinical Sciences, Lund University, SE, Lund, Sweden.
5
Lund Brain Injury Laboratory for Neurosurgical Research, Department of Clinical Sciences, Lund University, Lund, Sweden.
6
John van Geest Centre for Brain Repair, Forvie Site, Robinson Way, Cambridge, CB2 0PY, UK. mc469@cam.ac.uk.
7
The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK. mc469@cam.ac.uk.
8
John van Geest Centre for Brain Repair, Forvie Site, Robinson Way, Cambridge, CB2 0PY, UK. ilknur.ozen@med.lu.se.
9
Lund Brain Injury Laboratory for Neurosurgical Research, Department of Clinical Sciences, Lund University, Lund, Sweden. ilknur.ozen@med.lu.se.
10
Lund Brain Injury Laboratory for Neurosurgical Research, Wallenberg Neuroscience Center, Lund University, BMC A13, 221 84, Lund, Sweden. ilknur.ozen@med.lu.se.

Abstract

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, overproduction 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.

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