Somatostatin receptor subtypes 1 and 4 redundantly regulate neprilysin, the major amyloid beta-degrading enzyme, in brain

Alzheimer9s disease (AD) brains are characterized by increased levels of the pathogenic amyloid beta (Abeta) peptide, which accumulates into extracellular plaques. Finding a way to lower Abeta levels is fundamental for the prevention and treatment of AD. Neprilysin is the major Abeta-degrading enzyme which is regulated by the neuropeptide somatostatin. Here we used a combination of in vitro and in vivo approaches to identify the subtype specificity of the five somatostatin receptors (SSTs) expressed in the brain, involved in the regulation of neprilysin. Using a battery of Sst double knockout (dKO) mice we show that neprilysin is regulated by SST1 and SST4 in a redundant manner. Sst1 and Sst4 dKO mice exhibit a specific decrease of presynaptic neprilysin in the Lacunosum molecular layer. Moreover, a genetic deficiency of Sst1 and Sst4 in amyloid beta precursor protein (App) knock-in mice, an AD mouse model, aggravates the Abeta pathology in the hippocampus. As a first proof of concept towards an Abeta-lowering strategy involving neprilysin, we demonstrate that treatment with an agonist selective for SST1 and SST4 ameliorates the Abeta pathology and improves cognition in the App knock-in AD mouse model.