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

BackgroundAlzheimer's disease (AD) brains are characterized by increased levels of the pathogenic amyloid-β (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.ObjectiveWe here aimed at identifying the subtype specificity of the five somatostatin receptors (SSTs) expressed in the brain, involved in the regulation of neprilysin.MethodsWe used a combination of in vitro and in vivo approaches using a battery of generated Sst double knockout (dKO) mice. We investigated SST specificity of neprilysin regulation using primary neuronal cultures in combination with SST agonist treatments and neprilysin activity measurements. Brains from Sst dKO mice were analyzed for neprilysin and Aβ by biochemical and immunohistological means. Amyloid-beta precursor protein (App) knock-in mice were treated with SST1,4 agonist and its effects on neprilysin and Aβ were assessed by immunostaining and ELISA.ResultsWe 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 App knock-in mice aggravates the Aβ pathology in hippocampus. As a first proof of concept towards an Aβ-lowering strategy involving neprilysin, we demonstrate that treatment with an SST1,4 agonist ameliorates the Aβ pathology.ConclusionsSST1 and SST4 redundantly regulate neprilysin in the hippocampus where it controls Aβ metabolism.