Liraglutide can reverse memory impairment, synaptic loss and reduce plaque load in aged APP/PS1 mice, a model of Alzheimer's disease

• Published in: Neuropharmacology 2014-01, Vol.76, p.57-67
• Main Authors: McClean, Paula L., Hölscher, Christian
• Format: Article
• Language: English
• Subjects: Aging - drug effects; Aging - pathology; Alzheimer Disease - complications; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Alzheimer Disease - psychology; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Animals; Cell Count; Cognition; Disease Models, Animal; GLP-1; Glucagon-Like Peptide 1 - analogs & derivatives; Glucagon-Like Peptide 1 - pharmacology; Glucagon-Like Peptide 1 - therapeutic use; Incretins; Inflammation; Inflammation - drug therapy; Insulin; Liraglutide; Long-Term Potentiation - drug effects; Long-Term Potentiation - physiology; Male; Memory; Memory - drug effects; Memory Disorders - complications; Memory Disorders - drug therapy; Mice; Mice, Transgenic; Nerve Degeneration - complications; Nerve Degeneration - drug therapy; Nerve Degeneration - metabolism; Neurodegeneration; Neuroprotection; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Plaque, Amyloid - complications; Plaque, Amyloid - drug therapy; Stem cells; Stem Cells - drug effects; Synapse; Synapses - drug effects; Synapses - pathology
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2013.08.005

Type 2 diabetes is a risk factor in the development of Alzheimer's disease (AD). It has been shown that insulin signalling is desensitised in the brains of AD patients. The incretin hormone Glucagon-like peptide-1 (GLP-1) facilitates insulin signalling, and long-lasting analogues such as liraglutide (Victoza®) are on the market as type 2 diabetes treatments. We have previously shown that liraglutide improved cognitive function, reduced amyloid plaque deposition, inflammation, overall APP and oligomer levels and enhanced LTP when injected peripherally for two months in 7 month old APPswe/PS1ΔE9 (APP/PS1) mice. This showed that liraglutide has preventive effects at the early stage of AD development. The current study investigated whether Liraglutide would have restorative effects in late-stage Alzheimer's disease in mice. Accordingly, 14-month-old APP/PS1 and littermate control mice were injected with Liraglutide (25 nmol/kg bw) ip. for 2 months. Spatial memory was improved by Liraglutide-treatment in APP/PS1 mice compared with APP/PS1 saline-treated mice. Overall plaque load was reduced by 33%, and inflammation reduced by 30%, while neuronal progenitor cell count in the dentate gyrus was increased by 50%. LTP was significantly enhanced in APP/PS1 liraglutide-treated mice compared with APP/PS1 saline mice, corroborated with increased synapse numbers in hippocampus and cortex. Total brain APP and beta-amyloid oligomer levels were reduced in Liraglutide-treated APP/PS1 mice while IDE levels were increased. These results demonstrate that Liraglutide not only has preventive properties, but also can reverse some of the key pathological hallmarks of AD. Liraglutide is now being tested in clinical trials in AD patients. This article is part of the Special Issue entitled ‘The Synaptic Basis of Neurodegenerative Disorders’. •Liraglutide protected 14-month-old APP/PS1 mice in the key markers for AD.•The overall plaque load in the brain was reduced by 33%.•The chronic inflammation response was reduced by 30%.•Neuronal progenitor cell count in the dentate gyrus was increased by 50%.•Total brain APP and beta-amyloid oligomer levels were reduced.