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

Claire S Durrant,Karsten Ruscher,Olivia Sheppard,Ilknur Özen,Michael P Coleman

doi:10.1038/s41419-020-2288-4

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.

Highlights

Alzheimer’s disease (AD) is closely associated with alterations in the vascular system[1]
We studied P7 TgCRND8 mouse post mortem cortex to determine whether a mutant huAPP transgene, leads to pathological changes in the organisation of the vascular network and endothelial cell physiology during postnatal development (30,31) (Fig. 1)
In this study, we explored the relationship between Aβ processing, NOTCH signalling and pathological angiogenesis in cortical tissue from huAPP transgenic mice

Summary

Introduction

Alzheimer’s disease (AD) is closely associated with alterations in the vascular system[1]. Multiple studies in humans and animal models have described pathological vascular changes in AD2, including disruption to the neurovascular unit[3] and blood–brain barrier[4], increased microvessel density[3,5,6], arteriolar and venular tortuosity[7,8] and vascular Aβ accumulation[9]. Such changes will likely compromise the effective delivery of oxygen and nutrients to the brain, so understanding whether vascular alterations are a cause or consequence of aspects of AD. Despite widespread interest in the role of brain vasculature in AD, little is known about how amyloid-induced vascular changes alter pathological sprouting angiogenesis

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Conclusion