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 in spatial learning and memory in AD model mice (Meilandt et al., 2009). It was also reported that cerebral Aβ concentration was too low to be degraded by neprilysin (Shibata et al., 2000). The affinity of neprilysin for its physiological substrates (e.g., enkephalins, tachykinins, atrial natriuretic peptide) is within the millimolar range (Hersh and Morihara, 1986), while the levels of Aβ in the brain are normally in the nanomolar range and up to 1 μM/kg even in APP-transgenic mice (Hsiao et al., 1996). Thus, only small concentrations of Aβ will likely bind to neprilysin under physiological and pathological conditions. Many issues should be solved to proceed to drug development of neprilysin activators.
