Proteomics

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Regulating hippocampal levels of Alzheimer´s disease-related proteins with a brain-penetrating somatostatin peptide

ABSTRACT: Plaques consisting of amyloid-β (Aβ) in the brain are characteristic for patients with Alzheimer´s disease. Aβ is enzymatically generated of the amyloid precursor protein. Furthermore, neprilysin, an Aβ-degrading enzyme, and its main activator the neuropeptide somatostatin (SST) are downregulated in Alzheimer´s disease. In the fusion protein SST-scFv8D3, SST is recombinantly fused to a blood-brain barrier transporter. The aim of this study was to study the effect of SST-scFv8D3 on the proteome of different brain regions in order to elucidate the anti-Alzheimer´s disease effects of this construct. SST-scFv8D3 and phosphate buffered saline (PBS) respectively were injected into transgenic mice of an Alzheimer´s disease model with the Swedish mutation (AβPP KM670/671NL) every 36 hours (three times in total). Homogenates of the hippocampus, the cerebellum and the rest of the cerebrum were lysed. Afterwards, filter aided tryptic digestion was performed. The resulting peptides were analyzed using LC-UDMSE. The data was searched against a randomized mouse database and label-free quantification analysis was done. In total 1869 proteins were found. Only the proteome of the hippocampus was affected by the treatment with SST-scFv8D3. 55 proteins were significantly up and 105 down regulated compared to the PBS treated mice. Among these were mitochondrial and synaptic proteins as well as some involved in neuron´s development indicating anti-Alzheimer disease effects of SST-scFv8D3 and supporting the future use of SST-scFv8D3 as a treatment option.

INSTRUMENT(S): Synapt MS

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Erik Jansson  

LAB HEAD: Erik T. Jansson

PROVIDER: PXD022221 | Pride | 2021-06-28

REPOSITORIES: Pride

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Publications

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 F   Sandbaumhüter Friederike A FA   Chourlia Aikaterini A   Metzendorf Nicole G NG   Morrison Jamie I JI   Syvänen Stina S   Andrén Per E PE   Jansson Erik T ET   Hultqvist Greta G  

ACS chemical neuroscience 20210625 13

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 activi  ...[more]

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