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.
Highlights
Glucagon-like peptide 1 (GLP-1) receptor agonists have prominent insulin-dependent glycemic effects and are currently in use for the treatment of type 2 diabetes [1]
As peripherally administered GLP-1 receptor agonists can access the brain [2,3,4] and GLP-1 receptors are widely expressed in the CNS [5,6,7], this has led to an increasing appreciation that GLP-1 receptor agonists may have important central effects beyond glucose homeostasis and weight control
As a consequence of the discovery of neurotrophic, neuroprotective, neurogenesis and memory-enhancing effects induced by enhanced GLP-1 receptor function [8,9,10], considerable efforts have in the last decade been made to assess possible disease-modifying properties of GLP-1 receptor agonist treatment in neurodegenerative diseases [11,12]
Summary
Glucagon-like peptide 1 (GLP-1) receptor agonists have prominent insulin-dependent glycemic effects and are currently in use for the treatment of type 2 diabetes [1]. In support of reduced vulnerability to amyloidosis-associated neurotoxicity, subchronic (3 weeks) exendin-4 treatment has been shown to reduce soluble β-amyloid levels, to lower cortical amyloid plaque load and improve memory performance in a double transgenic APP/PS1 mouse model of amyloidosis [21]. In this transgenic model, liraglutide and lixisenatide have been demonstrated to evoke similar effects on memory function and plaque burden [22,23], as well as improving markers of synaptic plasticity and to stimulate neuroproliferative activity [23,24,25]
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