Aβ catabolism is regulated by a series of degrading enzymes as well as glial cells, such as astrocytes and microglia, in the brain parenchyma (Vardy et al., 2005). Among them, neprilysin has received much attention (Iwata et al., 2000). Previous reports have described impaired Aβ degradation in neprilysin-deficient mice (Iwata et al., 2001) and amelioration of Aβ pathology in APP-transgenic mice, when injected with viral vector expressing human neprilysin gene (Marr et al., 2003; Iwata et al., 2004, 2013). Levels of neprilysin mRNA were found to be significantly lower in the hippocampus and middle temporal gyrus of AD brains compared with normal control patients (Yasojima et al., 2001). Decreased neprilysin activity was also associated with CAA (Miners et al., 2006). Thus, the up-regulation of cerebral neprilysin activity could potentially be targeted in the treatment of AD. Indeed, a somatostatin receptor agonist has recently been shown to increase neprilysin activity and decrease Aβ levels in senescence-accelerated mice (Sandoval et al., 2012). However, Meilandt et al. reported that an 11-fold greater neprilysin overexpression failed to reduce pathogenic Aβ oligomers and improve deficits
