| Autor: |
Rofo F; Protein Drug Design, Faculty of Pharmacy, Biomedical Centre 591, Uppsala University, 75124 Uppsala, Sweden., Sandbaumhüter FA; Medical Mass Spectrometry, Department of Pharmaceutical Biosciences, Biomedical Centre 591, Uppsala University, 75124 Uppsala, Sweden., Chourlia A; Protein Drug Design, Faculty of Pharmacy, Biomedical Centre 591, Uppsala University, 75124 Uppsala, Sweden., Metzendorf NG; Protein Drug Design, Faculty of Pharmacy, Biomedical Centre 591, Uppsala University, 75124 Uppsala, Sweden., Morrison JI; Protein Drug Design, Faculty of Pharmacy, Biomedical Centre 591, Uppsala University, 75124 Uppsala, Sweden., Syvänen S; Department of Public Health and Caring Sciences, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden., Andrén PE; Medical Mass Spectrometry, Department of Pharmaceutical Biosciences, Biomedical Centre 591, Uppsala University, 75124 Uppsala, Sweden.; Science for Life Laboratory, Spatial Mass Spectrometry, Biomedical Centre 591, Uppsala University, 75124 Uppsala, Sweden., Jansson ET; Medical Mass Spectrometry, Department of Pharmaceutical Biosciences, Biomedical Centre 591, Uppsala University, 75124 Uppsala, Sweden., Hultqvist G; Protein Drug Design, Faculty of Pharmacy, Biomedical Centre 591, Uppsala University, 75124 Uppsala, Sweden. |
| Abstrakt: |
Alzheimer's disease is the most common neurodegenerative disorder characterized by the pathological aggregation of amyloid-β (Aβ) peptide. A potential therapeutic intervention in Alzheimer's disease is to enhance Aβ degradation by increasing the activity of Aβ-degrading enzymes, including neprilysin. The somatostatin (SST) peptide has been identified as an activator of neprilysin. Recently, we demonstrated the ability of a brain-penetrating SST peptide (SST-scFv8D3) to increase neprilysin activity and membrane-bound Aβ42 degradation in the hippocampus of mice overexpressing the Aβ-precursor protein with the Swedish mutation (APPswe). Using LC-MS, we further evaluated the anti-Alzheimer's disease effects of SST-scFv8D3. Following a triple intravenous injection of SST-scFv8D3, the LC-MS analysis of the brain proteome revealed that the majority of downregulated proteins consisted of mitochondrial proteins regulating fatty acid oxidation, which are otherwise upregulated in APPswe mice compared to wild-type mice. Moreover, treatment with SST-scFv8D3 significantly increased hippocampal levels of synaptic proteins regulating cell membrane trafficking and neuronal development. Finally, hippocampal concentrations of growth-regulated α (KC/GRO) chemokine and degradation of neuropeptide-Y were elevated after SST-scFv8D3 treatment. In summary, our results demonstrate a multifaceted effect profile in regulating mitochondrial function and neurogenesis following treatment with SST-scFv8D3, further suggesting the development of Alzheimer's disease therapies based on SST peptides. |
