The Diabetes Drug Liraglutide Prevents Degenerative Processes in a Mouse Model of Alzheimer's Disease

By P. McClean, V. Parthsarathy, E. Faivre, C. Hölscher. Journal of Neuroscience, 2011

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Type 2 diabetes is a risk factor for Alzheimer's disease, most likely linked to an impairment of insulin signaling in the brain. The incretin hormone glucagon-like peptide-1 (GLP-1) facilitates insulin signaling, and novel long-lasting GLP-1 analogs, such as liraglutide, are on the market as diabetes therapeutics. GLP-1 has been shown to have neuroprotective properties in vitro and in vivo. Here we tested the effects of peripherally injected liraglutide in an Alzheimer mouse model, APPswe/PS1ΔE9 (APP/PS1). Liraglutide was shown to cross the blood–brain barrier in an acute study. Liraglutide was injected for 8 weeks at 25 nmol/kg body weight i.p. once daily in 7-month-old APP/PS1 and wild-type littermate controls. In APP/PS1 mice, liraglutide prevented memory impairments in object recognition and water maze tasks, and prevented synapse loss and deterioration of synaptic plasticity in the hippocampus, commonly observed in this model. Overall β-amyloid plaque count in the cortex and dense-core plaque numbers were reduced by 40–50%, while levels of soluble amyloid oligomers were reduced by 25%. The inflammation response as measured by activated microglia numbers was halved in liraglutide-treated APP/PS1 mice. Numbers of young neurons in the dentate gyrus were increased in APP/PS1 mice with treatment. Liraglutide treatment had little effect on littermate control mice, whose behavior was comparable to wild-type saline controls; however, synaptic plasticity was enhanced in the drug group. Our results show that liraglutide prevents key neurodegenerative developments found in Alzheimer's disease, suggesting that GLP-1 analogs represent a novel treatment strategy for Alzheimer's disease.

Subfields: Cellular and Molecular Neuroscience, Endocrinology, Diabetes and Metabolism, Physiology

View Paper: https://www.semanticscholar.org/paper/2954b47adc5df1a215103c521666841381f59425

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Citations in the corpus

Inflammation, Defective Insulin Signaling, and Mitochondrial Dysfunction as Common Molecular Denominators Connecting Type 2 Diabetes to Alzheimer Disease (2014, background): “Exendin-4 and liraglutide also restore impaired insulin signaling in the brains of a transgenic mouse model of AD, improving cognition, decreasing Ab accumulation, and attenuating eIF2a-P (37,54,99).”
Microglia and neurodegeneration: The role of systemic inflammation (2013, background): “, 2011), and diabetes (McClean et al., 2011).”
The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. (2014, neutral): “Nevertheless, some studies have shown that GLP-1 analogs seem to pass the BBB, although no clear details as to areas targeted or mechanisms have been reported (26, 27).”
Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. (2012, background): “Metformin (120, 165) and 2 GLP-1 mimetics (121, 124, 125, 165, 166) are antidiabetic agents approved by the FDA without restriction; all have excellent safety profiles, readily cross the bloodbrain barrier, and raise insulin-induced IR and IRS-1 activation.”