Format

Send to

Choose Destination
Brain Res. 2016 Mar 1;1634:158-170. doi: 10.1016/j.brainres.2015.12.052. Epub 2015 Dec 31.

The GLP-1 receptor agonist liraglutide reduces pathology-specific tau phosphorylation and improves motor function in a transgenic hTauP301L mouse model of tauopathy.

Author information

1
Gubra, Agern Allé 1, DK-2970 Hoersholm, Denmark. Electronic address: hbh@gubra.dk.
2
Gubra, Agern Allé 1, DK-2970 Hoersholm, Denmark.
3
reMYND NV, Gaston Greenslaan 1, B-3001 Leuven-Heverlee, Belgium.
4
Diabetes Research, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Maaloev, Denmark.
5
Gubra, Agern Allé 1, DK-2970 Hoersholm, Denmark. Electronic address: niels@gubra.dk.

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.

KEYWORDS:

Alzheimer’s disease; GLP-1 receptor agonist; Liraglutide; Phosphorylated tau; Tauopathy; hTauP301L transgenic mouse

PMID:
26746341
DOI:
10.1016/j.brainres.2015.12.052
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center