AI Article Synopsis
- Amyloid beta peptides are linked to blood-brain barrier issues and irregular blood vessel formation in Alzheimer's Disease, but the exact mechanisms are still unclear.
- In human-APP transgenic mouse models, increased endothelial sprouting relies on β-secretase (BACE1) processing of APP, which is associated with reduced NOTCH3/JAG1 signaling.
- BACE1 inhibition can normalize excessive endothelial changes and restore NOTCH3 signaling, suggesting it may be a promising therapeutic target for abnormal blood vessel growth in Alzheimer's.
Article 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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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005019 | PMC |
| http://dx.doi.org/10.1038/s41419-020-2288-4 | DOI Listing |
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