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

Durrant, Claire S., Ruscher, Karsten, Sheppard, Olivia, Coleman, Michael P., Özen, Ilknur·2020·Cell Death & Disease
DOI 10.1038/s41419-020-2288-4PMC PMC7005019

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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, 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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  • Changes in BACE1 activity have been associated with physiological functions including maintenance of the blood-brain barrier, angiogenesis, protection against obesity, immune and antimicrobial properties, inflammatory response, and tumor suppression.

    “In addition to its neuronal roles, changes in BACE1 activity have been associated with physiological functions including maintenance of the blood–brain barrier (BBB), angiogenesis, protection against obesity, immune and antimicrobial properties, inflammatory response, and tumor suppression.”

    From BACE1: More than just a β‐secretase (2022) · cites this paper as [46]

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Metadata

Authors
Durrant, C. S., Ruscher, K., Sheppard, O., Coleman, M. P., & Özen, I.
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2020-02-06
Volume
11
Issue
2
ISSN
2041-4889
DOI
10.1038/s41419-020-2288-4
PMC
PMC7005019
Cited by
39
References
12
Language
en
Licence
Funders
  • Alzheimer's Research UK (ARUK-PG2015-24)
  • John and Lucille Van Geest Foundation

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