Beta secretase 1-dependent amyloid precursor protein processing promotes excessive vascular sprouting through NOTCH3 signalling
(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.
(Less)
- author
- Durrant, Claire S. ; Ruscher, Karsten LU ; Sheppard, Olivia ; Coleman, Michael P. and Özen, Ilknur LU
- organization
- publishing date
- 2020
- 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
-
- pmid:32029735
- scopus:85079038312
- 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
- 2024-09-18 18:34:38
@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}}, }