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ABSTRACT
The amyloid beta (Aβ) peptide is central to the pathogenesis of Alzheimer's disease (AD). Insights into Aβ-interacting proteins are critical for understanding the molecular mechanisms underlying Aβ-mediated toxicity. We recently undertook an in-depth in vitro interrogation of the Aβ1–42 interactome using human frontal lobes as the biological source material and taking advantage of advances in mass spectrometry performance characteristics. These analyses uncovered the small cyclic neuropeptide somatostatin (SST) to be the most selectively enriched binder to oligomeric Aβ1–42. Subsequent validation experiments revealed that SST interferes with Aβ fibrillization and promotes the formation of Aβ assemblies characterized by a 50–60 kDa SDS-resistant core. The distributions of SST and Aβ overlap in the brain and SST has been linked to AD by several additional observations. This perspective summarizes this body of literature and draws attention to the fact that SST is one of several neuropeptide hormones that acquire amyloid properties before their synaptic release. The latter places the interaction between SST and Aβ among an increasing number of observations that attest to the ability of amyloidogenic proteins to influence each other. A model is presented which attempts to reconcile existing data on the involvement of SST in the AD etiology.
Abbreviations
| Aβ | = | amyloid beta peptide |
| AD | = | Alzheimer's disease |
| ADDL | = | Aβ-derived diffusible ligand |
| CNS | = | central nervous system |
| CSF | = | cerebrospinal fluid |
| CST | = | cortistatin |
| mAβ | = | monomeric Aβ |
| NFT | = | neurofibrillary tangle |
| oAβ | = | oligomeric Aβ |
| PPSST | = | preprosomatostatin |
| PrP | = | prion protein |
| RSP | = | regulated secretory pathway |
| α-SN | = | alpha-synuclein |
| SDS | = | sodium dodecyl sulfate |
| SST | = | somatostatin |
| SST14 | = | somatostatin–14 |
| SSTR | = | SST receptor |
| TGN | = | trans-Golgi-network |
| ThT | = | thioflavin T |
Disclosure statement
HaW and GS hold a provisionary US patent on amyloid-beta binding polypeptides based in part on results of the original paper underlying this perspective article (filing number 62/451,309). The other authors declare that no competing interests exist.
Acknowledgments
We gratefully acknowledge generous ongoing support by the Borden Rosiak family and the Arnold Irwin family.
