Sökning: onr:"swepub:oai:DiVA.org:uu-426301" >
Enhanced neprilysin...
Enhanced neprilysin-mediated degradation of hippocampal A beta 42 with a somatostatin peptide that enters the brain
-
- Rofo, Fadi (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
-
- Yilmaz, Canan Ugur (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
-
- Metzendorf, Nicole G., 1979- (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
-
visa fler...
-
- Gustavsson, Tobias (författare)
- Uppsala universitet,Geriatrik
-
- Beretta, Chiara (författare)
- Uppsala universitet,Geriatrik
-
- Erlandsson, Anna (författare)
- Uppsala universitet,Geriatrik
-
- Sehlin, Dag, 1976- (författare)
- Uppsala universitet,Geriatrik
-
- Syvänen, Stina (författare)
- Uppsala universitet,Geriatrik
-
- Nilsson, Per (författare)
- Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden.
-
- Hultqvist, Greta, 1980- (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Protein drug design
-
visa färre...
-
(creator_code:org_t)
- IVYSPRING INT PUBL, 2021
- 2021
- Engelska.
-
Ingår i: Theranostics. - : IVYSPRING INT PUBL. - 1838-7640. ; 11:2, s. 789-804
- Relaterad länk:
-
https://doi.org/10.7...
-
visa fler...
-
https://uu.diva-port... (primary) (Raw object)
-
https://doi.org/10.7...
-
https://urn.kb.se/re...
-
https://doi.org/10.7...
-
visa färre...
Abstract
Ämnesord
Stäng
- 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
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Nyckelord
- Amyloid-beta (A beta)
- blood-brain barrier (BBB)
- neprilysin
- somatostatin (SST)
- transferrin receptor (TfR)
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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