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Wide-Ranging Effects on the Brain Proteome in a Transgenic Mouse Model of Alzheimer’s Disease Following Treatment with a Brain-Targeting Somatostatin Peptide
[Image: see text] 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, in...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8291608/ https://www.ncbi.nlm.nih.gov/pubmed/34170117 http://dx.doi.org/10.1021/acschemneuro.1c00303 |
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author | Rofo, Fadi Sandbaumhüter, Friederike A. Chourlia, Aikaterini Metzendorf, Nicole G. Morrison, Jamie I. Syvänen, Stina Andrén, Per E. Jansson, Erik T. Hultqvist, Greta |
author_facet | Rofo, Fadi Sandbaumhüter, Friederike A. Chourlia, Aikaterini Metzendorf, Nicole G. Morrison, Jamie I. Syvänen, Stina Andrén, Per E. Jansson, Erik T. Hultqvist, Greta |
author_sort | Rofo, Fadi |
collection | PubMed |
description | [Image: see text] 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. |
format | Online Article Text |
id | pubmed-8291608 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-82916082021-07-21 Wide-Ranging Effects on the Brain Proteome in a Transgenic Mouse Model of Alzheimer’s Disease Following Treatment with a Brain-Targeting Somatostatin Peptide Rofo, Fadi Sandbaumhüter, Friederike A. Chourlia, Aikaterini Metzendorf, Nicole G. Morrison, Jamie I. Syvänen, Stina Andrén, Per E. Jansson, Erik T. Hultqvist, Greta ACS Chem Neurosci [Image: see text] 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. American Chemical Society 2021-06-25 /pmc/articles/PMC8291608/ /pubmed/34170117 http://dx.doi.org/10.1021/acschemneuro.1c00303 Text en © 2021 The Authors. Published by American Chemical Society Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Rofo, Fadi Sandbaumhüter, Friederike A. Chourlia, Aikaterini Metzendorf, Nicole G. Morrison, Jamie I. Syvänen, Stina Andrén, Per E. Jansson, Erik T. Hultqvist, Greta Wide-Ranging Effects on the Brain Proteome in a Transgenic Mouse Model of Alzheimer’s Disease Following Treatment with a Brain-Targeting Somatostatin Peptide |
title | Wide-Ranging Effects on the Brain Proteome in a Transgenic
Mouse Model of Alzheimer’s Disease Following Treatment with
a Brain-Targeting Somatostatin Peptide |
title_full | Wide-Ranging Effects on the Brain Proteome in a Transgenic
Mouse Model of Alzheimer’s Disease Following Treatment with
a Brain-Targeting Somatostatin Peptide |
title_fullStr | Wide-Ranging Effects on the Brain Proteome in a Transgenic
Mouse Model of Alzheimer’s Disease Following Treatment with
a Brain-Targeting Somatostatin Peptide |
title_full_unstemmed | Wide-Ranging Effects on the Brain Proteome in a Transgenic
Mouse Model of Alzheimer’s Disease Following Treatment with
a Brain-Targeting Somatostatin Peptide |
title_short | Wide-Ranging Effects on the Brain Proteome in a Transgenic
Mouse Model of Alzheimer’s Disease Following Treatment with
a Brain-Targeting Somatostatin Peptide |
title_sort | wide-ranging effects on the brain proteome in a transgenic
mouse model of alzheimer’s disease following treatment with
a brain-targeting somatostatin peptide |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8291608/ https://www.ncbi.nlm.nih.gov/pubmed/34170117 http://dx.doi.org/10.1021/acschemneuro.1c00303 |
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