期刊
THERANOSTICS
卷 11, 期 2, 页码 789-804出版社
IVYSPRING INT PUBL
DOI: 10.7150/thno.50263
关键词
Amyloid-beta (A beta); blood-brain barrier (BBB); neprilysin; somatostatin (SST); transferrin receptor (TfR)
资金
- Swedish Research Council
- Hedlunds stiftelse
- Ake Wibergs stiftelse
- Ahlen-stiftelsen
- Jeanssons stiftelser
- Magnus Bergvalls stiftelse
- Hallstens forskningsstiftelse
- Hjarnfonden
- Alzheimerfonden
- Knut and Alice Wallenberg Foundation
This study successfully increased the brain concentration of neprilysin by fusing SST to a BBB transporter, leading to a significant degradation of membrane-bound A beta in AD mice. The findings suggest a potential treatment paradigm targeting specific areas affected by the disease.
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.
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