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

Durrant, Claire S. ; Ruscher, Karsten LU ; Sheppard, Olivia ; Coleman, Michael P. and Özen, Ilknur LU (2020) In Cell Death and Disease 11(2).
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... (More)

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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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Cell Death and Disease
volume
11
issue
2
article number
98
publisher
Nature Publishing Group
external identifiers
  • scopus:85079038312
  • pmid:32029735
ISSN
2041-4889
DOI
10.1038/s41419-020-2288-4
language
English
LU publication?
yes
id
72315472-c47f-4ab6-bee0-e4d49e0f2a4c
date added to LUP
2020-02-19 13:24:01
date last changed
2020-09-23 08:06:14
@article{72315472-c47f-4ab6-bee0-e4d49e0f2a4c,
  abstract     = {<p>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.</p>},
  author       = {Durrant, Claire S. and Ruscher, Karsten and Sheppard, Olivia and Coleman, Michael P. and Özen, Ilknur},
  issn         = {2041-4889},
  language     = {eng},
  number       = {2},
  publisher    = {Nature Publishing Group},
  series       = {Cell Death and Disease},
  title        = {Beta secretase 1-dependent amyloid precursor protein processing promotes excessive vascular sprouting through NOTCH3 signalling},
  url          = {http://dx.doi.org/10.1038/s41419-020-2288-4},
  doi          = {10.1038/s41419-020-2288-4},
  volume       = {11},
  year         = {2020},
}