abstract
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Background: Alzheimer's disease (AD) brains are characterized by increased levels of the pathogenic amyloid-ß (Aß) peptide, which accumulates into extracellular plaques. Finding a way to lower Aß levels is fundamental for the prevention and treatment of AD. Neprilysin is the major Aß degrading enzyme which is regulated by the neuropeptide somatostatin. Objective: We here aimed at identifying the subtype specificity of the five somatostatin receptors (SSTs) expressed in the brain, involved in the regulation of neprilysin. Methods: We 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 Aß 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 Aß were assessed by immunostaining and ELISA. Results: We show that neprilysin is regulated by SST
1 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 Aß pathology in hippocampus. As a first proof of concept towards an Aß-lowering strategy involving neprilysin, we demonstrate that treatment with an SST1,4 agonist ameliorates the Aß pathology. Conclusions: SST1 and SST4 redundantly regulate neprilysin in the hippocampus where it controls Aß metabolism. © The Author(s) 2025