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

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 proangiogenic 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.

The physiological roles of tau and Aβ: implications for Alzheimer’s disease pathology and therapeutics

“…In vitro, Aβ can inhibit endothelial cell capillary formation in a dose-dependent manner and stimulates capillary degeneration at high concentrations [201]. At low concentrations, however, Aβ has been found to promote endothelial cell proliferation [27], induce formation of capillary-like structures [27], and increase vessel density in brain slice cultures [64]. In vivo studies using chick [27] or zebrafish embryos [40] and adult zebrafish retinas [51] find that Aβ peptides increase capillary density and induce formation of sprouting tip cells.…”

“…Whilst low levels of Aβ seem important for maintaining physiological vascularisation, increasing levels of Aβ in early AD have been shown to promote pathological angiogenesis, resulting in excessive vascularisation and disturbance to normal blood flow [21,58,64]. Excessive cleavage of APP, or direct inhibitory action of Aβ, may overwhelm or inhibit the activity of γ-secretase, thus reducing its availability to cleave Notch proteins, known angiogenesis inhibitors [27,64]. Indeed, γ-secretase inhibitor treatment increases angiogenesis and vascularisation in a range of model systems [40].…”

“…Indeed, γ-secretase inhibitor treatment increases angiogenesis and vascularisation in a range of model systems [40]. Lowering Aβ levels, through immunisation against Aβ [20] or BACE1 inhibition [64], restores normal vascular patterns in AD models. Indeed, a meta-analysis of clinical trials reports that people with AD receiving immunisations against Aβ 1-42, show a significant reduction of endothelial cells and vascular density [20].…”

Microvascular Alterations in Alzheimer's Disease

“…Since vessel density in APP/PS1 mice at 18-months does not differ between transgenic and age-matched controls (Hooijmans et al, 2007 ), it is reasonable to assume that the impaired glymphatic clearance at 3–13 months is not attributable to vessel loss. Mice models do experience changes in microvascular morphology at early time points prior to vascular loss (Durrant et al, 2020 ). It is conceivable that these morphological changes reflect dysfunctional vasculature, which could contribute to impaired Aβ clearance.…”

Epigenetic profiling of Italian patients identified methylation sites associated with hereditary transthyretin amyloidosis

“…APP processing occurs via three proteolytic cleavages caused by α- β- and γ-secretase [ 35 ]. In non-amyloidogenic processes, α- and γ-secretases lead to the production of a smaller P3 fragment and APP intracellular domain, while, in the amyloidogenic pathway, β-secretase and γ-secretase produce amyloid-beta [ 35 – 39 ]. Our results also showed a high-confidence interaction between APP and TTR.…”