Research ReportSomatostatin receptor subtype-4 agonist NNC 26-9100 mitigates the effect of soluble Aβ42 oligomers via a metalloproteinase-dependent mechanism

•Somatostatin receptor subtype-4 agonist NNC 26-9100 enhanced learning in SAMP8 mice.•NNC 26-9100 decreased soluble Aβ42 oligomer levels in cortical tissue of SAMP8 mice.•Similar impact on learning and soluble Aβ42 oligomer levels shown in Tg2576 mice.•NNC 26-9100 action was blocked by the metalloproteinase inhibitor phosphoramidon.•NNC 26-9100 learning and Aβ42 oligomer affect shows metalloproteinase-dependence.

Soluble amyloid-β peptide (Aβ) oligomers have been hypothesized to be primary mediators of Alzheimer's disease progression. In this regard, reduction of soluble Aβ-oligomers levels within the brain may provide a viable means in which to treat the disease. Somatostatin receptor subtype-4 (SSTR4) agonists have been proposed to reduce Aβ levels in the brain via enhancement of enzymatic degradation. Herein we evaluated the effect of selective SSTR4 agonist NNC 26-9100 on the changes in learning and soluble Aβ42 oligomer brain content with and without co-administration of the M13-metalloproteinase family enzyme-inhibitor phosphoramidon, using the senescence-accelerated mouse prone-8 (SAMP8) model. NNC 26-9100 treatment (0.2 µg i.c.v. in 2 µL) improved learning, which was blocked by phosphoramidon (1 and 10 mM, respectively). NNC 26-9100 decreased total soluble Aβ42, an effect which was blocked by phosphoramidon (10 mM). Extracellular, intracellular, and membrane fractions were then isolated from cortical tissue and assessed for soluble oligomer alterations. NNC 26-9100 decreased the Aβ42 trimeric (12 kDa) form within the extracellular and intracellular fractions, and produced a band-split effect of the Aβ42 hexameric (25 kDa) form within the extracellular fraction. These effects were also blocked by phosphoramdon (1 and 10 mM, respectively). Subsequent evaluation of NNC 26-9100 in APPswe Tg2576 transgenic mice showed a similar learning improvement and corresponding reduction in soluble Aβ42 oligomers within extracellular, intracellular, and membrane fractions. These data support the hypothesis that NNC 26-9100 reduces soluble Aβ42 oligomers and enhances learning through a phosphoramidon-sensitive metalloproteinase-dependent mechanism.