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Enhanced neprilysin...
Enhanced neprilysin-mediated degradation of hippocampal A beta 42 with a somatostatin peptide that enters the brain
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- Rofo, Fadi (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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- Yilmaz, Canan Ugur (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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- Metzendorf, Nicole G., 1979- (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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- Gustavsson, Tobias (author)
- Uppsala universitet,Geriatrik
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- Beretta, Chiara (author)
- Uppsala universitet,Geriatrik
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- Erlandsson, Anna (author)
- Uppsala universitet,Geriatrik
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- Sehlin, Dag, 1976- (author)
- Uppsala universitet,Geriatrik
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- Syvänen, Stina (author)
- Uppsala universitet,Geriatrik
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- Nilsson, Per (author)
- Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden.
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- Hultqvist, Greta, 1980- (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Protein drug design
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(creator_code:org_t)
- IVYSPRING INT PUBL, 2021
- 2021
- English.
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In: Theranostics. - : IVYSPRING INT PUBL. - 1838-7640. ; 11:2, s. 789-804
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https://doi.org/10.7...
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https://uu.diva-port... (primary) (Raw object)
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https://doi.org/10.7...
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Keyword
- Amyloid-beta (A beta)
- blood-brain barrier (BBB)
- neprilysin
- somatostatin (SST)
- transferrin receptor (TfR)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Rofo, Fadi
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Yilmaz, Canan Ug ...
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Metzendorf, Nico ...
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Gustavsson, Tobi ...
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Beretta, Chiara
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Erlandsson, Anna
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show more...
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Sehlin, Dag, 197 ...
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Syvänen, Stina
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Nilsson, Per
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Hultqvist, Greta ...
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Neurosciences
- Articles in the publication
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Theranostics
- By the university
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Uppsala University