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J Pathol. 2018 May;245(1):85-100. doi: 10.1002/path.5056. Epub 2018 Apr 2.

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.

Author information

1
Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
2
School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
3
Centre for Neuroscience Studies, Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
4
Animal Care Service, Queen's University, Kingston, Ontario, Canada.
5
Departament of Neurobiology, Fluminense Federal University, Niteroi, Brazil.
6
Department of Pathology, Faculty of Medicine, Hospital Universitário Clementino Fraga Filho, UFRJ, Rio de Janeiro, Brazil.
7
Division of Biomed and Life Sciences, Faculty of Health and Medicine Lancaster University, Lancaster, UK.
8
Department of Neurobiology, Northwestern University, Evanston, Illinois, USA.
9
Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
10
Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

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. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

KEYWORDS:

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

PMID:
29435980
PMCID:
PMC5947670
DOI:
10.1002/path.5056
[Indexed for MEDLINE]
Free PMC Article

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