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
Ingår i deldatabas
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
Internetlänk
Hitta via bibliotek
Till lärosätets databas
- Av författaren/redakt...
-
Rofo, Fadi
-
Yilmaz, Canan Ug ...
-
Metzendorf, Nico ...
-
Gustavsson, Tobi ...
-
Beretta, Chiara
-
Erlandsson, Anna
-
visa fler...
-
Sehlin, Dag, 197 ...
-
Syvänen, Stina
-
Nilsson, Per
-
Hultqvist, Greta ...
-
visa färre...
- Om ämnet
-
- MEDICIN OCH HÄLSOVETENSKAP
-
MEDICIN OCH HÄLS ...
-
och Medicinska och f ...
-
och Neurovetenskaper
- Artiklar i publikationen
-
Theranostics
- Av lärosätet
-
Uppsala universitet