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Sökning: onr:"swepub:oai:DiVA.org:uu-426301" > Enhanced neprilysin...

  • Rofo, FadiUppsala universitet,Institutionen för farmaceutisk biovetenskap (författare)

Enhanced neprilysin-mediated degradation of hippocampal A beta 42 with a somatostatin peptide that enters the brain

  • Artikel/kapitelEngelska2021

Förlag, utgivningsår, omfång ...

  • IVYSPRING INT PUBL,2021
  • electronicrdacarrier

Nummerbeteckningar

  • LIBRIS-ID:oai:DiVA.org:uu-426301
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-426301URI
  • https://doi.org/10.7150/thno.50263DOI

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

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Klassifikation

  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • Background: Aggregation of the amyloid-beta (A beta) peptide is one of the main neuropathological events in Alzheimer's disease (AD). Neprilysin is the major enzyme degrading A beta, with its activity enhanced by the neuropeptide somatostatin (SST). SST levels are decreased in the brains of AD patients. The poor delivery of SST over the blood-brain barrier (BBB) and its extremely short half-life of only 3 min limit its therapeutic significance.Methods: We recombinantly fused SST to a BBB transporter binding to the transferrin receptor. Using primary neuronal cultures and neuroblastoma cell lines, the ability of the formed fusion protein to activate neprilysin was studied. SST-scFv8D3 was administered to mice overexpressing the A beta-precursor protein (A beta PP) with the Swedish mutation (APPswe) as a single injection or as a course of three injections over a 72 h period. Levels of neprilysin and A beta were quantified using an Enzyme-linked immunosorbent assay (ELISA). Distribution of SST-scFv8D3 in the brain, blood and peripheral organs was studied by radiolabeling with iodine-125.Results: The construct, SST-scFv8D3, exhibited 120 times longer half-life than SST alone, reached the brain in high amounts when injected intravenously and significantly increased the brain concentration of neprilysin in APPswe mice. A significant decrease in the levels of membrane-bound A beta 42 was detected in the hippocampus and the adjacent cortical area after only three injections.Conclusion: With intravenous injections of our BBB permeable SST peptide, we were able to significantly increase the levels neprilysin, an effect that was followed by a significant and selective degradation of membrane-bound A beta 42 in the hippocampus. Being that membrane-bound A beta triggers neuronal toxicity and the hippocampus is the central brain area in the progression of AD, the study has illuminated a new potential treatment paradigm with a promising safety profile targeting only the disease affected areas.

Ämnesord och genrebeteckningar

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • Yilmaz, Canan UgurUppsala universitet,Institutionen för farmaceutisk biovetenskap(Swepub:uu)canug148 (författare)
  • Metzendorf, Nicole G.,1979-Uppsala universitet,Institutionen för farmaceutisk biovetenskap(Swepub:uu)nineu226 (författare)
  • Gustavsson, TobiasUppsala universitet,Geriatrik(Swepub:uu)tobgu548 (författare)
  • Beretta, ChiaraUppsala universitet,Geriatrik(Swepub:uu)chibe560 (författare)
  • Erlandsson, AnnaUppsala universitet,Geriatrik(Swepub:uu)annafors (författare)
  • Sehlin, Dag,1976-Uppsala universitet,Geriatrik(Swepub:uu)daseh499 (författare)
  • Syvänen, StinaUppsala universitet,Geriatrik(Swepub:uu)stsyv838 (författare)
  • Nilsson, PerKarolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden. (författare)
  • Hultqvist, Greta,1980-Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Protein drug design(Swepub:uu)grhul102 (författare)
  • Uppsala universitetInstitutionen för farmaceutisk biovetenskap (creator_code:org_t)

Sammanhörande titlar

  • Ingår i:Theranostics: IVYSPRING INT PUBL11:2, s. 789-8041838-7640

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