title: The GLP-1 receptor agonist liraglutide reduces pathology-specific tau phosphorylation and improves motor function in a transgenic hTauP301L mouse model of tauopathy.
abstract: In addition to a prominent role in glycemic control, glucagon-like peptide 1 (GLP-1) receptor agonists exhibit neuroprotective properties. There is mounting experimental evidence that GLP-1 receptor agonists, including liraglutide, may enhance synaptic plasticity, counteract cognitive deficits and ameliorate neurodegenerative features in preclinical models of Alzheimer's disease (AD), predominantly in the context of β-amyloid toxicity. Here we characterized the effects of liraglutide in a transgenic mutant tau (hTauP301L) mouse tauopathy model, which develops age-dependent pathology-specific neuronal tau phosphorylation and neurofibrillary tangle formation with progressively compromised motor function (limb clasping). Liraglutide (500 µg/kg/day, s.c., q.d., n=18) or vehicle (n=18) was administered to hTauP301L mice for 6 months from the age of three months. Vehicle-dosed wild-type FVB/N mice served as normal control (n=17). The onset and severity of hind limb clasping was markedly different in liraglutide and vehicle-dosed transgenic mice. Clasping behavior was observed in 61% of vehicle-dosed hTauP301L mice with a 55% survival rate in 9-month old transgenic mice. In contrast, liraglutide treatment reduced the clasping rate to 39% of hTauP301L mice, and fully prevented clasping-associated lethality resulting in a survival rate of 89%. Stereological analyses demonstrated that hTauP301L mice exhibited hindbrain-dominant neuronal accumulation of phosphorylated tau closely correlated to the severity of clasping behavior. In correspondence, liraglutide treatment significantly reduced neuronal phospho-tau load by 61.9±10.2% (p<0.001) in hTauP301L mice, as compared to vehicle-dosed controls. In conclusion, liraglutide significantly reduced tau pathology in a transgenic mouse tauopathy model.
authors.affiliation: Gubra, Agern Allé 1, DK-2970 Hoersholm, Denmark. Electronic address: hbh@gubra.dk.
authors.forename: Henrik H
authors.initials: HH
authors.lastname: Hansen
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: Katrine
authors.initials: K
authors.lastname: Fabricius
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: 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. Electronic address: niels@gubra.dk.
authors.forename: Niels
authors.initials: N
authors.lastname: Vrang
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects; D005260:Female; D000069450:Liraglutide / Q000008:administration & dosage* / Q000097:blood; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010766:Phosphorylation; D020127:Recovery of Function / Q000187:drug effects*; D016019:Survival Analysis; D024801:Tauopathies / Q000378:metabolism* / Q000503:physiopathology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: C054369:MAPT protein, human; D018696:Neuroprotective Agents; D016875:tau Proteins; D000069450:Liraglutide; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
keywords: Alzheimer’s disease; GLP-1 receptor agonist; Liraglutide; Phosphorylated tau; Tauopathy; hTauP301L transgenic mouse