title: Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer's Disease.
abstract: One of the major histopathological hallmarks of Alzheimer's disease (AD) is cerebral deposits of extracellular β-amyloid peptides. Preclinical studies have pointed to glucagon-like peptide 1 (GLP-1) receptors as a potential novel target in the treatment of AD. GLP-1 receptor agonists, including exendin-4 and liraglutide, have been shown to promote plaque-lowering and mnemonic effects of in a number of experimental models of AD. Transgenic mouse models carrying genetic mutations of amyloid protein precursor (APP) and presenilin-1 (PS1) are commonly used to assess the pharmacodynamics of potential amyloidosis-lowering and pro-cognitive compounds. In this study, effects of long-term liraglutide treatment were therefore determined in two double APP/PS1 transgenic mouse models of Alzheimer's disease carrying different clinical APP/PS1 mutations, i.e. the 'London' (hAPPLon/PS1A246E) and 'Swedish' mutation variant (hAPPSwe/PS1ΔE9) of APP, with co-expression of distinct PS1 variants. Liraglutide was administered in 5 month-old hAPPLon/PS1A246E mice for 3 months (100 or 500 ng/kg/day, s.c.), or 7 month-old hAPPSwe/PS1ΔE9 mice for 5 months (500 ng/kg/day, s.c.). In both models, regional plaque load was quantified throughout the brain using stereological methods. Vehicle-dosed hAPPSwe/PS1ΔE9 mice exhibited considerably higher cerebral plaque load than hAPPLon/PS1A246E control mice. Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPPLon/PS1A246E and hAPPSwe/PS1ΔE9 mice. In conclusion, long-term liraglutide treatment exhibited no effect on cerebral plaque load in two transgenic mouse models of low- and high-grade amyloidosis, which suggests differential sensitivity to long-term liraglutide treatment in various transgenic mouse models mimicking distinct pathological hallmarks of AD.
authors.affiliation: Gubra, Agern Allé 1, DK-2970 Hoersholm, Denmark.
authors.forename: Henrik H
authors.initials: HH
authors.lastname: Hansen
authors.affiliation: Gubra, Agern Allé 1, DK-2970 Hoersholm, Denmark.
authors.forename: Katrine
authors.initials: K
authors.lastname: Fabricius
authors.affiliation: Gubra, Agern Allé 1, DK-2970 Hoersholm, Denmark.
authors.forename: Pernille
authors.initials: P
authors.lastname: Barkholt
authors.affiliation: Gubra, Agern Allé 1, DK-2970 Hoersholm, Denmark.
authors.forename: Pernille
authors.initials: P
authors.lastname: Kongsbak-Wismann
authors.affiliation: Gubra, Agern Allé 1, DK-2970 Hoersholm, Denmark.
authors.forename: Chantal
authors.initials: C
authors.lastname: Schlumberger
authors.affiliation: Gubra, Agern Allé 1, DK-2970 Hoersholm, Denmark.
authors.forename: Jacob
authors.initials: J
authors.lastname: Jelsing
authors.affiliation: reMYND NV, Gaston Greenslaan 1, B-3001 Leuven-Heverlee, Belgium.
authors.forename: Dick
authors.initials: D
authors.lastname: Terwel
authors.affiliation: reMYND NV, Gaston Greenslaan 1, B-3001 Leuven-Heverlee, Belgium.
authors.forename: Annelies
authors.initials: A
authors.lastname: Termont
authors.affiliation: Diabetes Research, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Maaloev, Denmark.
authors.forename: Charles
authors.initials: C
authors.lastname: Pyke
authors.affiliation: Diabetes Research, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Maaloev, Denmark.
authors.forename: Lotte Bjerre
authors.initials: LB
authors.lastname: Knudsen
authors.affiliation: Gubra, Agern Allé 1, DK-2970 Hoersholm, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Vrang
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000069450:Liraglutide / Q000494:pharmacology / Q000627:therapeutic use*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D058225:Plaque, Amyloid / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics*; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D016564:Amyloid beta-Protein Precursor; D007004:Hypoglycemic Agents; D053764:Presenilin-1; D000069450:Liraglutide; D000097789:Glucagon-Like Peptide-1 Receptor Agonists