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

View ORCID ProfileClaire S. Durrant, Karsten Ruscher, View ORCID ProfileOlivia Sheppard, View ORCID ProfileMichael P. Coleman, Ilknur Özen
doi: https://doi.org/10.1101/585489
Claire S. Durrant
John van Geest Centre for Brain Repair, Forvie Site, Robinson Way, Cambridge CB2 0PY, UKThe Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK
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Karsten Ruscher
Lund University, Skane University Hospital, Department of Clinical Sciences Lund, Neurosurgery, Lund, Sweden
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Olivia Sheppard
John van Geest Centre for Brain Repair, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK
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Michael P. Coleman
John van Geest Centre for Brain Repair, Forvie Site, Robinson Way, Cambridge CB2 0PY, UKThe Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK
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  • For correspondence: mc469@cam.ac.uk
Ilknur Özen
John van Geest Centre for Brain Repair, Forvie Site, Robinson Way, Cambridge CB2 0PY, UKTranslational Neurology Group, Department of Clinical Science, Lund University, 22184 Lund, Sweden
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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, 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.

Significance In this study, we show that targeting amyloid beta processing provides an opportunity to selectively target tip cell filopodia-driven angiogenesis and develop therapeutic targets for vascular dysfunction related to aberrant angiogenesis in AD. Our data provide the first evidence for a safe level of BACE1 inhibition that can normalize excess angiogenesis in AD, without inducing vascular deficits in healthy tissue. Our findings may pave the way for the development of new angiogenesis dependent therapeutic strategies in Alzheimer’s Disease.

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  • ↵# shared last authorship

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 21, 2019.
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Beta secretase 1-dependent amyloid precursor protein processing promotes excessive vascular sprouting through NOTCH3 signaling
Claire S. Durrant, Karsten Ruscher, Olivia Sheppard, Michael P. Coleman, Ilknur Özen
bioRxiv 585489; doi: https://doi.org/10.1101/585489
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Beta secretase 1-dependent amyloid precursor protein processing promotes excessive vascular sprouting through NOTCH3 signaling
Claire S. Durrant, Karsten Ruscher, Olivia Sheppard, Michael P. Coleman, Ilknur Özen
bioRxiv 585489; doi: https://doi.org/10.1101/585489

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