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

Soluble amyloid-beta peptide (A beta) oligomers have been hypothesized to be primary mediators of Alzheimer's disease progression. In this regard, reduction of soluble A beta-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 A beta 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 A beta(42) 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 mu g i.c.v. in 2 mu L) improved learning, which was blocked by phosphoramidon (1 and 10 mM, respectively). NNC 26-9100 decreased total soluble A beta(42), 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 A beta(42) trimeric (12 kDa) form within the extracellular and intracellular fractions, and produced a band-split effect of the A beta(42) 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 A beta(42) oligomers within extracellular, intracellular, and membrane fractions. These data support the hypothesis that NNC 26-9100 reduces soluble A beta(42) oligomers and enhances learning through a phosphoramidon-sensitive metalloproteinase-dependent mechanism. (c) 2013 Elsevier B.V. All rights reserved.