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

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.

Automated summary

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.