title: Lixisenatide, a drug developed to treat type 2 diabetes, shows neuroprotective effects in a mouse model of Alzheimer's disease.
abstract: Type 2 diabetes is a risk factor for developing Alzheimer's disease (AD). In the brains of AD patients, insulin signalling is desensitised. The incretin hormone Glucagon-like peptide-1 (GLP-1) facilitates insulin signalling, and analogues such as liraglutide are on the market as treatments for type 2 diabetes. We have previously shown that liraglutide showed neuroprotective effects in the APPswe/PS1ΔE9 mouse model of AD. Here, we test the GLP-1 receptor agonist lixisenatide in the same mouse model and compare the effects to liraglutide. After ten weeks of daily i.p. injections with liraglutide (2.5 or 25 nmol/kg) or lixisenatide (1 or 10 nmol/kg) or saline of APP/PS1 mice at an age when amyloid plaques had already formed, performance in an object recognition task was improved in APP/PS1 mice by both drugs at all doses tested. When analysing synaptic plasticity in the hippocampus, LTP was strongly increased in APP/PS1 mice by either drug. Lixisenatide (1 nmol/kg) was most effective. The reduction of synapse numbers seen in APP/PS1 mice was prevented by the drugs. The amyloid plaque load and dense-core Congo red positive plaque load in the cortex was reduced by both drugs at all doses. The chronic inflammation response (microglial activation) was also reduced by all treatments. The results demonstrate that the GLP-1 receptor agonists liraglutide and lixisenatide which are on the market as treatments for type 2 diabetes show promise as potential drug treatments of AD. Lixisenatide was equally effective at a lower dose compared to liraglutide in some of the parameters measured.
authors.affiliation: Clinical Translational Research and Innovation Centre, University of Ulster, Derry/Londonderry, BT47 6SB, Northern Ireland, UK.
authors.forename: Paula L
authors.initials: PL
authors.lastname: McClean
authors.affiliation: Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, LA1 4YQ, UK. Electronic address: c.holscher@lancaster.ac.uk.
authors.forename: Christian
authors.initials: C
authors.lastname: Hölscher
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D000069450:Liraglutide; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D058225:Plaque, Amyloid / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D013569:Synapses / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D000067758:Glucagon-Like Peptide-2 Receptor
chemical_list: D016564:Amyloid beta-Protein Precursor; D052216:Glucagon-Like Peptide 1; D000069450:Liraglutide; D018696:Neuroprotective Agents; D010455:Peptides; D053764:Presenilin-1; C545487:APP protein, human; C508853:PSEN1 protein, human; C479460:lixisenatide; D000067758:Glucagon-Like Peptide-2 Receptor
keywords: Cognition; GLP-1; Growth factor; Incretins; Inflammation; Insulin; Long-term potentiation; Memory; Neurodegeneration; Neuroprotection; Synapse