Glucagon-like peptide-1 cleavage product improves cognitive function in a mouse model of down syndrome

Stephen M. Day, Wenzhong Yang, Xin Wang, Jennifer E. Stern, Xueyan Zhou, Shannon L. Macauley, Tao Ma

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


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.

Original languageEnglish
Article numbere0031-19.2019
Issue number2
StatePublished - 2019

Bibliographical note

Funding Information:
Received January 23, 2019; accepted April 2, 2019; First published April 30, 2019. Author contributions: S.M.D. and T.M. designed research; S.M.D., W.Y., J.E.S., X.Z., and S.L.M. performed research; S.M.D., W.Y., X.W., J.E.S., S.L.M., and T.M. analyzed data; S.M.D. and T.M. wrote the paper. The authors declare no competing financial interests. This work was supported by National Institutes of Health Grants R01 AG055581, R01 AG056622 (T.M.), the Alzheimer’s Association grant NIRG-15-362799 (T.M.), and the BrightFocus Foundation Grant A2017457S. Correspondence should be addressed to Tao Ma at Copyright © 2019 Day et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

Publisher Copyright:
© 2019 Day et al.


  • Alzheimer’s disease
  • Down syndrome
  • GLP-1 (9-36)
  • LTP
  • Oxidative stress
  • Synaptic plasticity

ASJC Scopus subject areas

  • Neuroscience (all)


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