Abstract
The deposition of amyloid-β peptide (Aβ) causes the long-term pathological cascade of Alzheimer's disease (AD). Neprilysin is a rate-limiting peptidase, which participates in Aβ degradation in brain. As demonstrated by reverse genetics, the disruption of neprilysin gene causes an elevation in endogenous Aβ levels in the mouse brain in a gene-dose-dependent manner. Therefore, a reduction of neprilysin activity will contribute to Aβ deposition and thus to AD development. Neprilysin is localized at presynapses and on axons, and its expression levels are decreased at the terminal zones and on axons of the lateral perforant pathway and the mossy fibers with aging in mice, suggesting that local concentrations of Aβ are likely to be elevated at the sites, which play crucial roles on certain forms of learning and memory and are highly vulnerable to AD. Overexpression of neprilysin decreased both extracellular and intracellular Aβ levels in primary cortical neurons. These results indicate that up-regulation of neprilysin activity would be a relevant strategy for therapy and prevention through reduction of the Aβ levels. Recently, we have found that a certain neuropeptide regulates the expression of neprilysin in primary neurons. Since a number of receptors for neuropeptides are G-protein-coupled receptors, we would control brain Aβlevels pharmacologically by the manipulation of neprilysin activity.
