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

Alzheimer’s disease (AD) brains are characterized by increased levels of the pathogenic amyloid beta (Aβ) peptide, which accumulates into extracellular plaques. Finding a way to lower Aβ levels is fundamental for the prevention and treatment of AD. Neprilysin is the major Aβ 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 SST 1 and SST 4 in a redundant manner. Sst 1 and Sst 4 dKO mice exhibit a specific decrease of presynaptic neprilysin in the Lacunosum molecular layer. Moreover, a genetic deficiency of Sst 1 and Sst 4 in amyloid beta precursor protein ( App ) knock-in mice, an AD mouse model, aggravates the Aβ pathology in the hippocampus. As a first proof of concept towards an Aβ-lowering strategy involving neprilysin, we demonstrate that treatment with an agonist selective for SST 1 and SST 4 ameliorates the Aβ pathology and improves cognition in the App knock-in AD mouse model.