Somatostatin slows Aβ plaque deposition in aged APPNL-F/NL-F mice by blocking Aβ aggregation in a neprilysin-independent manner

The molecular underpinnings that govern the endoproteolytic release of the amyloid beta peptide (Abeta) from the amyloid precursor protein (APP) are now quite well understood. The same cannot be said for the events that precipitate the aggregation and amyloid deposition of Abeta in Alzheimer′s disease (AD). The 14-amino-acid cyclic neuroendocrine peptide somatostatin (SST-14) has long been thought of as playing a role, foremost by controlling the expression of the Abeta clearing enzyme neprilysin, and more recently by directly interacting with Abeta oligomers. Missing have been in vivo data in a relevant Abeta amyloidosis model. Here we addressed this shortcoming by crossing AppNL-F/NL-F mice with Sst-deficient mice of identical genetic background to assess if and how the presence of Sst influences key pathological hallmarks of Abeta amyloidosis that develop in AppNL-F/NL-F mice after 10 months of age. Surprisingly, we found that Sst had no influence on whole brain neprilysin transcript, protein or activity levels, an observation that cannot be accounted for by a compensatory upregulation of the Sst paralog, cortistatin (Cort), that we observed in 15-month-old Sst-deficient mice. The absence of Sst did lead to a subtle but significant increase in the density of cortical Abeta amyloid plaques. Follow-on western blot analyses of whole brain extracts indicated that Sst interferes with early steps of Abeta assembly that manifest in Sst null brains through the appearance of SDS-stable smears of 55-150 kDa. As expected, no effect of Sst on tau steady-state levels or its phosphorylation were observed. Results from this study are easier reconciled with an emerging body of data that point toward Sst affecting Abeta amyloid plaque formation through direct interference with Abeta aggregation rather than through its effects on neprilysin expression. ### Competing Interest Statement The authors have declared no competing interest.