title: The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease.
abstract: 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, APP(swe)/PS1(ΔE9) (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.
authors.affiliation: School of Biomedical Sciences, Ulster University, Coleraine BT52 1SA, Northern Ireland, United Kingdom.
authors.forename: Paula L
authors.initials: PL
authors.lastname: McClean
authors.forename: Vadivel
authors.initials: V
authors.lastname: Parthsarathy
authors.forename: Emilie
authors.initials: E
authors.lastname: Faivre
authors.forename: Christian
authors.initials: C
authors.lastname: Hölscher
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D000069450:Liraglutide; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000209:etiology* / Q000517:prevention & control*; D053764:Presenilin-1 / Q000235:genetics; D021641:Recognition, Psychology / Q000187:drug effects; D016708:Synaptophysin / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007004:Hypoglycemic Agents; C508853:PSEN1 protein, human; D053764:Presenilin-1; D016708:Synaptophysin; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1