Beta secretase 1-dependent amyloid precursor protein processing promotes excessive vascular sprouting through NOTCH3 signalling
Beta secretase 1-dependent amyloid precursor protein processing promotes excessive vascular sprouting through NOTCH3 signalling
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DOI：
10.1038/s41419-020-2288-4
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发表时间：
2020-02-06
影响因子：
9
通讯作者：
Ozen, Ilknur
中科院分区：
文献类型：
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作者：
Durrant, Claire S.;Ruscher, Karsten;Ozen, Ilknur
淀粉样β肽（Aβ）蛋白在阿尔茨海默病（AD）的血管病理学中发挥着关键作用，包括血脑屏障损伤和异常血管生成。尽管之前的工作已经证明了 Aβ 的促血管生成作用，但淀粉样前体蛋白 (APP) 加工和内皮血管生成信号级联在 AD 中相互作用的确切机制仍然是一个很大程度上尚未解决的问题。在此，我们报告人 APP 转基因小鼠 (TgCRND8) 组织中内皮出芽的增加依赖于 APP 的 β 分泌酶 (BACE1) 处理。 TgCRND8组织中较高水平的Aβ加工与NOTCH3/JAG1信号传导减少、内皮丝状伪足过度产生和血管周细胞数量增加同时发生。使用一种新颖的体外方法研究 TgCRND8 器官型脑切片培养物 (OBSC) 中的萌芽血管生成，我们发现 BACE1 抑制使过度的内皮丝状伪足形成正常化并恢复 NOTCH3 信号传导。这些数据为 BACE1 抑制作为 AD 异常血管生成的有效治疗靶点的潜力提供了第一个证据。
Amyloid beta peptides (A beta) 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 A beta, 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 A beta 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.