Abstract
BACE1 is the sole secretase for generating β-amyloid (Aβ) invivo and is being actively pursued as a drug target for the treatment of Alzheimer's disease. Transmembrane BACE1 exerts its biological activity by cleaving its membrane-bound cellular substrates. Here, we reveal that BACE1 directly regulates the level of membrane-anchored full-length Jagged1 (Jag1), a signaling molecule important for the control of neurogenesis and astrogenesis, via interaction with its cognate Notch receptor. We show that shedding of Jag1 is reduced in BACE1 null mice and upregulated Jag1 enhances Notch signaling via cell-cell juxtacrine interactions. Additional biochemical assays confirmed that overexpression of BACE1 enhanced cleavage of Jag1. Consequently, BACE1 null mice exhibit a significant increase in astrogenesis with a corresponding decrease in neurogenesis in their hippocampi during early development. Hence, BACE1 appears to function as a signaling protease that controls the balance of neurogenesis and astrogenesis via the Jag1-Notch pathway.
Highlights
BACE1 is widely recognized as the β–secretase that cleaves amyloid precursor protein (APP) at the N–terminal end of the β–amyloid peptide (Aβ) (Hussain et al, 1999; Lin et al, 2000; Sinha et al, 1999; Vassar et al, 1999; Yan et al, 1999)
We reveal that BACE1 directly regulates the level of membrane-anchored full length Jagged1 (Jag1), a signaling molecule important for the control of neurogenesis and astrogenesis, via interaction with its cognate Notch receptor
We show that shedding of Jag1 is reduced in BACE1-null mice and upregulated Jag1 enhances Notch signaling via cell-cell juxtacrine interactions
Summary
BACE1 is widely recognized as the β–secretase that cleaves amyloid precursor protein (APP) at the N–terminal end of the β–amyloid peptide (Aβ) (Hussain et al, 1999; Lin et al, 2000; Sinha et al, 1999; Vassar et al, 1999; Yan et al, 1999). Inhibition of BACE1 enzymatic activity is being actively investigated to treat or prevent AD. Because of this significant clinical application, knowledge concerning the broad physiological functions of BACE1 in the human brain is critical for understanding the full effects of BACE1 manipulations. BACE1-null mice have been widely utilized for this purpose. Initial reports demonstrated that BACE1-null mice are mostly viable and healthy, but recent studies show that BACE1null mice exhibit various abnormalities including hypomyelination (Hu et al, 2006; Hu et al, 2008; Willem et al, 2006), schizophrenia-like behaviors (Savonenko et al, 2008), epileptic seizures (Hitt et al, 2010; Hu et al, 2010), and retinal pathology associated with accumulation of age pigment (Cai et al, 2012). The abolished cleavage of BACE1 substrates, such as neuregulin-1 and voltage-gated sodium channel β-subunit, may account for the aforementioned phenotypes in BACE1-null mice (Hu et al, 2006; Hu et al, 2008; Hu et al, 2010; Kim et al, 2011; Willem et al, 2006)
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