Glucagon-Like Peptide-1 Cleavage Product Improves Cognitive Function in a Mouse Model of Down Syndrome

eNeuro. 2019 May 15;6(2):ENEURO.0031-19.2019. doi: 10.1523/ENEURO.0031-19.2019. Print 2019 Mar/Apr.

Abstract

Currently there is no effective therapy available for cognitive impairments in Down syndrome (DS), one of the most prevalent forms of intellectual disability in humans associated with the chromosomes 21 trisomy. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that maintains glucose homeostasis by stimulating insulin secretion. Its natural cleavage product GLP-1 (9-36) lacks insulinotropic effects and has a low binding affinity for GLP-1 receptors; thus, GLP-1 (9-36) has historically been identified as an inactive metabolite. Conversely, recent work has demonstrated interesting physiological properties of GLP-1 (9-36) such as cardioprotection and neuroprotection. We have previously shown that GLP-1 (9-36) administration enhances neuronal plasticity in young WT mice and ameliorates cognitive deficits in a mouse model of Alzheimer's disease. Here, we report that systemic administration of GLP-1 (9-36) in Ts65Dn DS model mice of either sex resulted in decreased mitochondrial oxidative stress in hippocampus and improved dendritic spine morphology, increase of mature spines and reduction of immature spines. Importantly, these molecular alterations translated into functional changes in that long-term potentiation failure and cognitive impairments in TsDn65 DS model mice were rescued with GLP-1 (9-36) treatment. We also show that chronic GLP-1 (9-36) treatment did not alter glucose tolerance in either WT or DS model mice. Our findings suggest that GLP-1 (9-36) treatment may have therapeutic potential for DS and other neurodegenerative diseases associated with increased neuronal oxidative stress.

Keywords: Alzheimer’s disease; Down syndrome; GLP-1 (9-36); LTP; oxidative stress; synaptic plasticity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Avoidance Learning / drug effects*
  • Behavior, Animal / drug effects
  • Cognitive Dysfunction / drug therapy*
  • Dendritic Spines / drug effects*
  • Disease Models, Animal
  • Down Syndrome / drug therapy*
  • Female
  • Glucagon-Like Peptide 1 / administration & dosage
  • Glucagon-Like Peptide 1 / analogs & derivatives*
  • Glucagon-Like Peptide 1 / pharmacology
  • Glucose Tolerance Test
  • Hippocampus / drug effects*
  • Long-Term Potentiation / drug effects*
  • Male
  • Mice
  • Mice, Transgenic
  • Neuronal Plasticity / drug effects*
  • Nootropic Agents / administration & dosage
  • Nootropic Agents / pharmacology*
  • Oxidative Stress / drug effects*
  • Spatial Memory / drug effects*

Substances

  • Nootropic Agents
  • glucagon-like peptide-1 (9-36)-amide
  • Glucagon-Like Peptide 1