4.6 Article

Wide-Ranging Effects on the Brain Proteome in a Transgenic Mouse Model of Alzheimer's Disease Following Treatment with a Brain-Targeting Somatostatin Peptide

Journal

ACS CHEMICAL NEUROSCIENCE
Volume 12, Issue 13, Pages 2529-2541

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.1c00303

Keywords

Alzheimer's disease; amyloid-beta; proteomics; somatostatin; SST-scFv8D3; LC-MS

Funding

  1. Swedish Research Council (Medicine and Health) [201803320, 2019-01885, 2017-02413]
  2. Swedish Research Council (Natural and Engineering Science) [2018-05501, 2018-03988]
  3. Swedish Foundation for Strategic Research [RIF14-0078, ICA16-0010]
  4. Swedish Brain Foundation [FO2018-0292, ALZ2019-0029]
  5. Science for Life Laboratory
  6. Jeanssons stiftelser
  7. Alzheimerfonden
  8. Hedlunds stiftelse
  9. Olle Engqvist stiftelse
  10. Ahlen-stiftelsen
  11. Torsten Soderbergs stiftelse
  12. Magnus Bergvalls stiftelse
  13. Vinnova
  14. Knut and Alice Wallenberg Foundation
  15. Ake Wibergs stiftelse
  16. Formas [2019-01885] Funding Source: Formas
  17. Swedish Foundation for Strategic Research (SSF) [ICA16-0010] Funding Source: Swedish Foundation for Strategic Research (SSF)
  18. Swedish Research Council [2018-05501, 2019-01885, 2017-02413, 2018-03988] Funding Source: Swedish Research Council
  19. Vinnova [2018-03988] Funding Source: Vinnova

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SST-scFv8D3 increases neprilysin activity and promotes the degradation of membrane-bound Aβ42 in Alzheimer's disease, while also regulating mitochondrial function and neurogenesis in the hippocampus of mice.
Alzheimer's disease is the most common neurodegenerative disorder characterized by the pathological aggregation of amyloid-beta (A beta) peptide. A potential therapeutic intervention in Alzheimer's disease is to enhance A beta degradation by increasing the activity of A beta-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 A beta 42 degradation in the hippocampus of mice overexpressing the A beta-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 a (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.

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