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• W4377029103 abstract "<b>Abstract ID 53923</b> <b>Poster Board 137</b> Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairments and brain amyloid-beta (Aβ) aggregation. Neprilysin (NEP) is a primary Aβ-degrading enzyme, activated by the neuropeptide somatostatin (ssT) through a receptor mediated action (Saito et al., 2005, Nat Med 11(4):434-439). Of the five ssT receptors, the subtype-4 (ssTR4) shows the greatest promise for AD treatment targeting. ssTR4 has optimal brain localization, being highly expressed in neurons of the neocortex, and hippocampus (Viollet et al., 2008, Mol Cell Endocrinol 286(1-2):75-87). We previously showed ssTR4 agonist actions increase spatial and recognition memory in <i>S</i>enescence Accelerated Mouse-Prone 8 (SAMP8) and APPswe mouse models of AD, with capacity to reduce Aβ-oligomer protein expression (Sandoval et al., 2012 Eur J Pharmacol 683(1-3):116-124; Sandoval et al., 2013, Brain Res 1520:145-56). Herein, we evaluated the novel ssTR4 agonist SM-I-26 on memory behavior and NEP activity in SAMP8 mice. SM-I-26 has high ssTR4 affinity (Ki=12 nM), selectivity (>400-fold selective over other ssTR subtypes), and activity (EC50=17 nM). Male 12-month-old SAMP8 mice were administered 0.01, 0.1, or 1.0 μg (i.c.v.) of SM-I-26 or vehicle for memory retention testing using the T-maze foot-shock avoidance test (memory retention 1-week post-injection, n = 7-8/group). NEP activity was tested at 1.0 μg (i.c.v.) against vehicle control in cortical and hippocampal tissue 24-h post injection (n = 7/group). SM-I-26 improved behavioral retention of the T-maze shock avoidance task in a dose-responsive manner (<i>P</i><0.0001, one-way ANOVA), with 0.1 and 1.0 μg SM-I-26 significantly reducing the mean trials to criterion when compared to vehicle (<i>P</i><0.0001, Dunnet’s T3). Within cortical tissue, SM-I-26 increased NEP activity (<i>P</i> < 0.05, independent t-test) compared to vehicle controls. A similar but non-significant trend between SM-I-26 and NEP activity was observed in hippocampal tissue. Data shows i.c.v. administration of the ssTR4 agonist SM-I-26 improves memory behavior in SAMP8 mice and increases NEP activity in primary tissues associated with AD impairments. The potential of a ssTR4 agonist therapeutic for AD treatment is supported by this work. This work has been supported by the National Institutes of Health, National Institute on Aging, R01AG047858." @default.
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• W4377029103 date "2023-05-18" @default.
• W4377029103 modified "2023-09-29" @default.
• W4377029103 title "Novel Somatostatin Receptor Subtype-4 Agonist Enhances Memory and Neprilysin Enzyme Activity in Senescence Accelerated Mouse-Prone 8 Model of Cognitive Decline" @default.
• W4377029103 doi "https://doi.org/10.1124/jpet.122.539230" @default.
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