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

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’ (hAPP(Lon/)PS1(A246E)) and ‘Swedish’ mutation variant (hAPP(Swe)/PS1(ΔE9)) of APP, with co-expression of distinct PS1 variants. Liraglutide was administered in 5 month-old hAPP(Lon/)PS1(A246E) mice for 3 months (100 or 500 ng/kg/day, s.c.), or 7 month-old hAPP(Swe)/PS1(ΔE9) 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 hAPP(Swe)/PS1(ΔE9) mice exhibited considerably higher cerebral plaque load than hAPP(Lon/)PS1(A246E) control mice. Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPP(Lon)/PS1(A246E) and hAPP(Swe)/PS1(ΔE9) 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.