Abstract
β-Site APP-cleaving enzyme 1 (BACE1) inhibition is considered one of the most promising therapeutic strategies for Alzheimer's disease, but current BACE1 inhibitors also block BACE2. As the localization and function of BACE2 in the brain remain unknown, it is difficult to predict whether relevant side effects can be caused by off-target inhibition of BACE2 and whether it is important to generate BACE1-specific inhibitors. Here, we show that BACE2 is expressed in discrete subsets of neurons and glia throughout the adult mouse brain. We uncover four new substrates processed by BACE2 in cultured glia: vascular cell adhesion molecule 1, delta and notch-like epidermal growth factor-related receptor, fibroblast growth factor receptor 1, and plexin domain containing 2. Although these substrates were not prominently cleaved by BACE2 in healthy adult mice, proinflammatory TNF induced a drastic increase in BACE2-mediated shedding of vascular cell adhesion molecule 1 in CSF. Thus, although under steady-state conditions the effect of BACE2 cross-inhibition by BACE1-directed inhibitors is rather subtle, it is important to consider that side effects might become apparent under physiopathological conditions that induce TNF expression.
Highlights
Β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is considered the major therapeutic target for Alzheimer’s disease (AD) (Cole & Vassar, 2007; Vassar et al, 2014; Yan & Vassar, 2014; Barão et al, 2016)
Synaptophysin (Syp), glutamate aspartate transporter (Glast), and myelin basic protein (Mbp) were used as specific markers for neurons, astrocytes, and oligodendrocytes, respectively, demonstrating that Bace2 expression can be detected in all three cell types (Fig 1A–C)
The lining of the lateral ventricle is the only brain area showing Bace2 expression in astrocytes (Fig 1E), whereas in oligodendrocytes, especially in young animals, Bace2 is found throughout the fiber tracts (Fig 1F)
Summary
Β-site APP-cleaving enzyme 1 (BACE1) is considered the major therapeutic target for Alzheimer’s disease (AD) (Cole & Vassar, 2007; Vassar et al, 2014; Yan & Vassar, 2014; Barão et al, 2016). The development and evaluation proceed cautiously as BACE1 can cleave numerous other substrates besides amyloid precursor protein (APP) (Kuhn et al, 2012; Zhou et al, 2012; Dislich et al, 2015) These substrates have been linked to synaptic plasticity (Wiera & Mozrzymas, 2015; Hu et al, 2016; Munro et al, 2016; Pigoni et al, 2016), myelination (Hu et al, 2006; Willem et al, 2006; Fleck et al, 2013; Van Bebber et al, 2013), and axonal outgrowth (Wright et al, 2007; Hitt et al, 2012; Barão et al, 2015) among the most studied functions
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