Regulation of neprilysin activity in the brain

We recently demonstrated that neprilysin regulates synapse-associated Ap oligomers that impair in vivo neuronal plasticity and cognitive functions (Huang et al. 2006). These observations suggest that up-regulation of neprilysin activity in AD brains is likely to contribute to improvement of cognitive functions. Since the gene therapy approach, which requires surgical procedures, is not yet realistic for clinical application to humans, we have sought a pharmacological means to selectively up-regulate brain neprilysin activity as a new therapeutic candidate (Saito et al. 2003). The rationale for this strategy was based on the fact that at least two cell type-specific ligands capable of up-regulating neprilysin activity have been identified: opioids for monocytes (Wang et al. 1998) and substance P for bone marrow cells (Joshi et al. 2001) as part of a negative feedback mechanism. It is notable that receptors for these ligands are G proteincoupled receptors (GPCRs). We found that somatostatin (SST) regulates the metabolism of Ap peptide in the brain via the modulation of proteolytic degradation catalyzed by neprilysin. Among various effector candidates, only SST up-regulated neprilysin activity in primary cortical neurons. A genetic deficiency of SST altered hippocampal neprilysin activity/localization and increased the quantity of a hydrophobic 42mer form of Ap, Ap42, in a manner similar to presenilin gene mutations that cause familial AD (Saito et al., 2005). Due to these results, SST receptor(s) have now emerged as pharmacological target candidates for the prevention and treatment of AD (Iwata et al.2005).

Thus far, five SST receptor subtypes have been identified, all of which are GPCRs (Moller et al. 2003), the most suitable pharmacological target category of proteins in the history of pharmaceutical science. Among the five subtypes, types two and four may serve as primary candidate targets because they are relatively potently expressed in the neocortex and hippocampus (Bruno et al. 1992; Moller et al. 2003). Synthesis of bloodbrain barrier-permeable agonists that can distinguishbetween different receptor subtypes, which should not be an impossible task in modern medicinal chemistry (Moller et al. 2003), would make it possible to develop a medical application for our findings. Alternatively, the use of an "anti-dementia" compound such as FK960, which elevates hippocampal SST levels (Doggrell 2004) in brain, may provide another effective approach. One potential benefit of harnessing neprilysin activity by agonizing SST receptor(s), among other Ap-reducing strategies, is that, if used conservatively, it is unlikely to be accompanied by major adverse side effects. Obviously, optimum combination of this approach with others would generate maximum beneficial effect (Saido and Iwata, 2006).

The expression of SST in the brain is known to decline with age in various mammals, including rodents, apes and humans (Hayashi et al. 1997; Lu et al. 2004). In human brains, SST mRNA is one of approximately 50 transcripts, the expression of which significantly declines after the age of 40, among approximately 11,000 transcripts examined (Lu et al. 2004). This finding indicates that the aging-dependent reduction of SST expression in the brain is a biologically specific and universal process. A prominent decrease in SST also represents a pathological characteristic of AD (Davies et al. 1980). These facts, combined with our observations that SST regulates neuronal neprilysin activity, led us to propose the following scenario for the etiology of sporadic AD development (Hama and Saido 2005). First, the aging-dependent reduction of SST causes a decrease of neprilysin activity, which then causes the steady-state Ap levels in brain to increase. Chronic elevation of the Ap levels may result in further downregulation of SST levels (Davies et al. 1980), oxidative inactivation of neprilysin (Wang et al. 2003), and increased expression of APP and p-secretase, because APP is a stress- responsive protein (Storey and Capprai 1999) and because expression of both APP and p-secretase has been reported to increase in the relatively downstream cascade of AD development (Yasojima et al. 2001b; Li et al. 2004). These events form a vicious cycle leading to a catastrophic accumulation of Ap in the brain (Funato et al. 1998; Wang et al. 1999; Morishima-Kawashima et al. 2000). If this hypothesis turns out to be true, we will not only be able to understand the etiology of sporadic AD but will also have identified a primary strategic target for the prevention and treatment of AD.

David M. Holtzman

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