{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T17:45:22Z","timestamp":1790271922331,"version":"4.1.0"},"reference-count":38,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Alzheimer\u2019s Disease"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Alzheimer's disease (AD) brains are characterized by increased levels of the pathogenic amyloid-\u03b2 (A\u03b2) peptide, which accumulates into extracellular plaques. Finding a way to lower A\u03b2 levels is fundamental for the prevention and treatment of AD. Neprilysin is the major A\u03b2 degrading enzyme which is regulated by the neuropeptide somatostatin.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>We here aimed at identifying the subtype specificity of the five somatostatin receptors (SSTs) expressed in the brain, involved in the regulation of neprilysin.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We used a combination of\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      approaches using a battery of generated\n                      <jats:italic toggle=\"yes\">Sst<\/jats:italic>\n                      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\n                      <jats:italic toggle=\"yes\">Sst<\/jats:italic>\n                      dKO mice were analyzed for neprilysin and A\u03b2 by biochemical and immunohistological means. Amyloid-beta precursor protein (\n                      <jats:italic toggle=\"yes\">App<\/jats:italic>\n                      ) knock-in mice were treated with SST1,4 agonist and its effects on neprilysin and A\u03b2 were assessed by immunostaining and ELISA.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We show that neprilysin is regulated by SST\n                      <jats:sub>1<\/jats:sub>\n                      and SST\n                      <jats:sub>4<\/jats:sub>\n                      in a redundant manner.\n                      <jats:italic toggle=\"yes\">\n                        Sst\n                        <jats:sub>1<\/jats:sub>\n                      <\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">\n                        Sst\n                        <jats:sub>4<\/jats:sub>\n                      <\/jats:italic>\n                      dKO mice exhibit a specific decrease of presynaptic neprilysin in the Lacunosum molecular layer. Moreover, a genetic deficiency of\n                      <jats:italic toggle=\"yes\">Sst<\/jats:italic>\n                      <jats:sub>1<\/jats:sub>\n                      and\n                      <jats:italic toggle=\"yes\">\n                        Sst\n                        <jats:sub>4<\/jats:sub>\n                      <\/jats:italic>\n                      in\n                      <jats:italic toggle=\"yes\">App<\/jats:italic>\n                      knock-in mice aggravates the A\u03b2 pathology in hippocampus. As a first proof of concept towards an A\u03b2-lowering strategy involving neprilysin, we demonstrate that treatment with an SST1,4 agonist ameliorates the A\u03b2 pathology.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>SST1 and SST4 redundantly regulate neprilysin in the hippocampus where it controls A\u03b2 metabolism.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/13872877251392782","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T08:30:18Z","timestamp":1763541018000},"page":"651-666","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["Somatostatin receptor subtypes 1 and 4 regulate neprilysin, the major amyloid-\u03b2 degrading enzyme in brain"],"prefix":"10.1177","volume":"109","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6450-0870","authenticated-orcid":false,"given":"Per","family":"Nilsson","sequence":"first","affiliation":[{"name":"Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Saitama, Japan"},{"name":"Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"S\u00f6rgjerd","sequence":"additional","affiliation":[{"name":"Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Saitama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomasa","family":"Kakiya","sequence":"additional","affiliation":[{"name":"Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Saitama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Sasaguri","sequence":"additional","affiliation":[{"name":"Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Saitama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoto","family":"Watamura","sequence":"additional","affiliation":[{"name":"Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Saitama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4493-1478","authenticated-orcid":false,"given":"Lovisa","family":"Johansson","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9618-0533","authenticated-orcid":false,"given":"Makoto","family":"Shimozawa","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Tsubuki","sequence":"additional","affiliation":[{"name":"Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Saitama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhulin","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raul","family":"Loera-Valencia","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, Solna, Sweden"},{"name":"Department of Basic Sciences, Faculty of Medicine and Health Sciences, Tecnologico de Monterrey, Monterrey, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9536-9606","authenticated-orcid":false,"given":"Risa","family":"Takamura","sequence":"additional","affiliation":[{"name":"Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Saitama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Misaki","family":"Sekiguchi","sequence":"additional","affiliation":[{"name":"Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Saitama, 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