Abstract
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.
Highlights
Alzheimer’s disease is a progressive and multifactorial neurodegenerative disorder
We compared the brain proteome of Aβ-precursor protein with the Swedish mutation (APPswe) mice treated with SST-scFv8D3 with that of APPswe mice treated with phosphate buffered saline (PBS); hereafter, this is referred to as the treatment study
The second study aimed at comparing the brain proteome of untreated APPswe mice with that of WT controls; hereafter, this is referred to as the transgenic study
Summary
Alzheimer’s disease is a progressive and multifactorial neurodegenerative disorder. It is the most common cause of dementia. In the brain of Alzheimer’s patients, extracellular amyloid aggregates and intracellular neurofibrillary tangles are formed, leading to synaptic toxicity and neuronal death.[1] The pathological amyloid aggregation is formed by a 36−43 amino acid long peptide called amyloid-β (Aβ). The latter is generated by enzymatic digestion of the transmembrane protein, amyloid precursor protein (APP). Accumulation of Aβ can be attributed to the decline in the activity and/or levels of the Aβ-degrading enzymes, including neprilysin.[3]
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