Beta secretase 1-dependent amyloid precursor protein processing promotes excessive vascular sprouting through NOTCH3
Claire S Durrant1,2,3, Karsten Ruscher4,5, Olivia Sheppard1
1John van Geest Centre for Brain Repair, Forvie Site, Robinson Way, Cambridge, CB2 0PY, UK.
Cell Death & Disease
|February 8, 2020
Summary
In Alzheimer's disease, amyloid beta peptides drive abnormal blood vessel growth. Inhibiting BACE1 enzyme normalizes this growth and restores signaling, offering a potential therapeutic strategy.
Area of Science:
- Neuroscience
- Vascular Biology
- Biochemistry
Background:
- Amyloid beta (Aβ) peptides are implicated in Alzheimer's Disease (AD) vascular pathology.
- Aβ's role in blood-brain barrier dysfunction and aberrant angiogenesis is recognized.
- Mechanisms linking amyloid precursor protein (APP) processing and endothelial signaling in AD are unclear.
Purpose of the Study:
- To investigate the role of APP processing by β-secretase (BACE1) in endothelial sprouting in AD.
- To elucidate the interaction between Aβ production and NOTCH3/JAG1 signaling in aberrant angiogenesis.
- To evaluate BACE1 inhibition as a therapeutic target for AD-related vascular changes.
Main Methods:
- Utilized human-APP transgenic mouse (TgCRND8) models.
- Employed organotypic brain slice cultures (OBSCs) for in vitro angiogenesis studies.
- Assessed endothelial filopodia, vascular pericyte numbers, and NOTCH3/JAG1 signaling pathways.
Main Results:
- Increased endothelial sprouting in TgCRND8 mice is dependent on BACE1 processing of APP.
- Elevated Aβ levels correlated with decreased NOTCH3/JAG1 signaling and increased filopodia and pericytes.
- BACE1 inhibition in OBSCs normalized filopodia and restored NOTCH3 signaling.
Conclusions:
- BACE1-mediated APP processing drives aberrant angiogenesis in AD.
- BACE1 inhibition effectively reverses pathological angiogenesis and restores signaling in an AD model.
- BACE1 inhibition represents a promising therapeutic strategy for vascular complications in Alzheimer's Disease.
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