Wide-Ranging Effects on the Brain Proteome in a Transgenic Mouse Model of Alzheimer’s Disease Following Treatment with a Brain-Targeting Somatostatin Peptide
| Autor: | Aikaterini Chourlia, Jamie I. Morrison, Fadi Rofo, Friederike A. Sandbaumhüter, Greta Hultqvist, Erik T. Jansson, Nicole G. Metzendorf, Stina Syvänen, Per E. Andrén |
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| Rok vydání: | 2021 |
| Předmět: |
Genetically modified mouse
endocrine system Proteome LC−MS Physiology Cognitive Neuroscience SST-scFv8D3 Hippocampus Mice Transgenic amyloid-β somatostatin Hippocampal formation Pharmacology Biochemistry Amyloid beta-Protein Precursor Mice 03 medical and health sciences proteomics 0302 clinical medicine Alzheimer Disease Animals Neprilysin 030304 developmental biology 0303 health sciences Amyloid beta-Peptides Activator (genetics) Chemistry fungi Neurogenesis Neurosciences Brain Cell Biology General Medicine Alzheimer's disease amyloid-beta LC-MS Disease Models Animal Somatostatin Alzheimer’s disease Neurovetenskaper hormones hormone substitutes and hormone antagonists 030217 neurology & neurosurgery Research Article |
| Zdroj: | ACS Chemical Neuroscience |
| ISSN: | 1948-7193 |
| DOI: | 10.1021/acschemneuro.1c00303 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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