Somatostatin binds to the human amyloid β peptide and favors the formation of distinct oligomers

Abstract

The amyloid β peptide (Aβ) is a key player in the etiology of Alzheimer disease (AD), yet a systematic investigation of its molecular interactions has not been reported. Here we identified by quantitative mass spectrometry proteins in human brain extract that bind to oligomeric Aβ1-42 (oAβ1-42) and/or monomeric Aβ1-42 (mAβ1-42) baits. Remarkably, the cyclic neuroendocrine peptide somatostatin-14 (SST14) was observed to be the most selectively enriched oAβ1-42 binder. The binding interface comprises a central tryptophan within SST14 and the N-terminus of Aβ1-42. The presence of SST14 inhibited Aβ aggregation and masked the ability of several antibodies to detect Aβ. Notably, Aβ1-42, but not Aβ1-40, formed in the presence of SST14 oligomeric assemblies of 50 to 60 kDa that were visualized by gel electrophoresis, nanoparticle tracking analysis and electron microscopy. These findings may be relevant for Aβ-directed diagnostics and may signify a role of SST14 in the etiology of AD.DOI: http://dx.doi.org/10.7554/eLife.28401.001

Somatostatin and Neuropeptide Y in Cerebrospinal Fluid: Correlations With Amyloid Peptides Aβ1–42 and Tau Proteins in Elderly Patients With Mild Cognitive Impairment

“…The association between CSF Aβ 1–42 and SOM concentrations may be explained by the fact that Aβ seems to specially affect SOM neurons. SOM and Aβ 1–42 have complex physical interactions (Wang et al, 2017 ). Moreover SOM increases neprilysin activity involved in Aβ degradation (Saito et al, 2005 ; Epelbaum et al, 2009 ).…”

“…In experimental AD models, increasing expression of Aβ 1–42 with aging is associated with an early fall of SOM interneurons in the hippocampus followed by NPY-positive ones (Saiz-Sanchez et al, 2016 ) or a reverse pattern (Wilcock et al, 2008 ; Albuquerque et al, 2015 ). Remarkably, SOM (in its 14 amino-acid moiety) was recently observed to be the most selectively enriched oligomeric Aβ 1–42 binder (Wang et al, 2017 ). In addition, a low level of CSF SOM correlates with cognitive deficits in AD (Tamminga et al, 1987 ) while CSF NPY concentrations changes are not as well documented (Gabriel et al, 1993 ).…”

Histological characterization of interneurons in Alzheimer's disease reveals a loss of somatostatin interneurons in the temporal cortex

“…42 It may be speculated that a loss of SST-immunoreactive interneurons in AD, as seen in this study and others, may lead to a loss in Aβ degrading enzymes, including endothelin-converting enzyme ECE-2 and therefore reduced Aβ metabolism and clearance, 18 resulting in Aβ accumulation and induced cell death. 43 Through mass spectrometry studies the most pronounced peptide to bind to Aβ was the cyclic neuroendocrine peptide SST-14, 44 highlighting the likely importance of the role of SST interaction with Aβ in AD pathology.…”

Somatostatin, Olfaction, and Neurodegeneration

“…Somatostatin dysfunction is involved early in memory deficits observed in mouse models and may be affected by Aβ 1−42 deposition (Schmid et al, 2016). Remarkably, SST is the main binder of Aβ 1−42 and can encourage the formation of different Aβ 1−42 oligomers by acquiring amyloid properties (Wang et al, 2017;Solarski et al, 2018). In agreement with this, SST and Aβ 1−42 levels in the cerebrospinal fluid seem to be correlated (Duron et al, 2018) and co-localization of both in the human brain, including the olfactory cortex, are widespread histological features .…”