| First Author | Durrant CS | Year | 2020 |
| Journal | Cell Death Dis | Volume | 11 |
| Issue | 2 | Pages | 98 |
| PubMed ID | 32029735 | Mgi Jnum | J:304213 |
| Mgi Id | MGI:6694421 | Doi | 10.1038/s41419-020-2288-4 |
| Citation | Durrant CS, et al. (2020) Beta secretase 1-dependent amyloid precursor protein processing promotes excessive vascular sprouting through NOTCH3 signalling. Cell Death Dis 11(2):98 |
| abstractText | Amyloid beta peptides (Abeta) 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 Abeta, 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 beta-secretase (BACE1) processing of APP. Higher levels of Abeta 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. |
