The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non-human primate model of Alzheimer's disease

Andre F. Batista, Leticia Forny-Germano, Julia R. Clarke, Natalia M. Lyra e Silva, Jordano Brito-Moreira, Susan E. Boehnke, Andrew Winterborn, Brian C. Coe, Ann Lablans, Juliana F. Vital, Suelen A. Marques, Ana M.B. Martinez, Matthias Gralle, Christian Holscher, William L. Klein, Jean Christophe Houzel, Sergio T. Ferreira, Douglas P. Munoz*, Fernanda G. De Felice

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

Abstract

Alzheimer's disease (AD) is a devastating neurological disorder that still lacks an effective treatment, and this has stimulated an intense pursuit of disease-modifying therapeutics. Given the increasingly recognized link between AD and defective brain insulin signaling, we investigated the actions of liraglutide, a glucagon-like peptide-1 (GLP-1) analog marketed for treatment of type 2 diabetes, in experimental models of AD. Insulin receptor pathology is an important feature of AD brains that impairs the neuroprotective actions of central insulin signaling. Here, we show that liraglutide prevented the loss of brain insulin receptors and synapses, and reversed memory impairment induced by AD-linked amyloid-β oligomers (AβOs) in mice. Using hippocampal neuronal cultures, we determined that the mechanism of neuroprotection by liraglutide involves activation of the PKA signaling pathway. Infusion of AβOs into the lateral cerebral ventricle of non-human primates (NHPs) led to marked loss of insulin receptors and synapses in brain regions related to memory. Systemic treatment of NHPs with liraglutide provided partial protection, decreasing AD-related insulin receptor, synaptic, and tau pathology in specific brain regions. Synapse damage and elimination are amongst the earliest known pathological changes and the best correlates of memory impairment in AD. The results illuminate mechanisms of neuroprotection by liraglutide, and indicate that GLP-1 receptor activation may be harnessed to protect brain insulin receptors and synapses in AD.

Original languageEnglish (US)
Pages (from-to)85-100
Number of pages16
JournalJournal of Pathology
Volume245
Issue number1
DOIs
StatePublished - May 2018

Keywords

  • Alzheimer's disease
  • GLP-1
  • PKA signaling
  • diabetes
  • insulin receptors
  • liraglutide
  • neurodegeneration
  • non-human primates
  • synapse damage
  • tau pathology

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Fingerprint Dive into the research topics of 'The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non-human primate model of Alzheimer's disease'. Together they form a unique fingerprint.

Cite this