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. 2011 Apr 27;31(17):6587-94.
doi: 10.1523/JNEUROSCI.0529-11.2011.

The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease

Paula L McClean  1 , Vadivel Parthsarathy, Emilie Faivre, Christian Hölscher
Affiliations

The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease

Paula L McClean et al. J Neurosci. .

Abstract

Type 2 diabetes is a risk factor for Alzheimer's disease, most likely linked to an impairment of insulin signaling in the brain. The incretin hormone glucagon-like peptide-1 (GLP-1) facilitates insulin signaling, and novel long-lasting GLP-1 analogs, such as liraglutide, are on the market as diabetes therapeutics. GLP-1 has been shown to have neuroprotective properties in vitro and in vivo. Here we tested the effects of peripherally injected liraglutide in an Alzheimer mouse model, APP(swe)/PS1(ΔE9) (APP/PS1). Liraglutide was shown to cross the blood-brain barrier in an acute study. Liraglutide was injected for 8 weeks at 25 nmol/kg body weight i.p. once daily in 7-month-old APP/PS1 and wild-type littermate controls. In APP/PS1 mice, liraglutide prevented memory impairments in object recognition and water maze tasks, and prevented synapse loss and deterioration of synaptic plasticity in the hippocampus, commonly observed in this model. Overall β-amyloid plaque count in the cortex and dense-core plaque numbers were reduced by 40-50%, while levels of soluble amyloid oligomers were reduced by 25%. The inflammation response as measured by activated microglia numbers was halved in liraglutide-treated APP/PS1 mice. Numbers of young neurons in the dentate gyrus were increased in APP/PS1 mice with treatment. Liraglutide treatment had little effect on littermate control mice, whose behavior was comparable to wild-type saline controls; however, synaptic plasticity was enhanced in the drug group. Our results show that liraglutide prevents key neurodegenerative developments found in Alzheimer's disease, suggesting that GLP-1 analogs represent a novel treatment strategy for Alzheimer's disease.

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Figures

Figure 1.
Figure 1.
Effect of saline and liraglutide treatment on recognition memory in an object recognition task. In the object recognition task, two identical objects were shown to mice for 10 min, after 56 d treatment with either 0.9% saline or liraglutide (25 nm/kg bw). After a 3 h interval, mice were exposed to one novel and one familiar object. Shown is the recognition index, which is the percentage of time spent exploring the novel object versus the overall exploration time. Liraglutide treatment made no difference to the learning ability of wild-type (wt) mice (A, B), with overall difference scores comparable (C). In contrast, liraglutide rescued the recognition memory of APP/PS1 mice (E), with controls unable to discriminate between novel and familiar objects (D). Overall difference scores were significantly increased in APP/PS1 liraglutide-treated mice (F) (Student's t test, *p < 0.05, **p < 0.01; all groups n = 12).
Figure 2.
Figure 2.
Liraglutide-treated APP/PS1 mice demonstrate improved memory in Morris water maze learning task. After 56 d treatment with 0.9% saline or liraglutide (25 nm/kg bw), mice were exposed to a Morris water maze learning paradigm involving 4 d acquisition, followed by a probe trial. Mice then received 4 d reversal training (with platform location moved) followed by a reversal probe trial. No appreciable differences were observed in the learning behavior of wild-type mice in normal (A, B) and reversal (C, D) water maze training and probe trials, despite a reduced escape latency on day 1 of reversal training (C). Liraglutide-treated APP/PS1 group learned the task faster in the acquisition phase, on days 3 and 4 (E), and remembered the location of the platform after the reversal probe trial (F, inset), showed no difference in the reversal acquisition phase (G), but showed good memory in the probe task (H, inset) (Student's t test, p = 0.0465), while the saline APP/PS1 group did not. *p < 0.05, **p < 0.01, ***p < 0.001, all groups n = 12.
Figure 3.
Figure 3.
Liraglutide protects LTP in APP/PS1 and wild-type mice. A, B, Liraglutide injected chronically for 56 d clearly protected LTP in area CA1 of the hippocampus in both wild-type (A) and APP/PS1 mice (B) (two-way ANOVA, p < 0.001). C, Paired-pulse facilitation demonstrates that liraglutide-treated mice have increased facilitation at 50, 80, 160, and 200 ms, compared with control; *p < 0.05, **p < 0.01 versus control, n = 7. HFS, High-frequency stimulus.
Figure 4.
Figure 4.
Histological hallmarks of AD are improved with liraglutide. A–C, After chronic treatment with 0.9% saline or liraglutide (25 nm/kg bw), the number of plaques in the cortex and hippocampus of liraglutide-treated APP/PS1 mice was halved. D–F, The number of Congo red-positive dense core plaques was reduced to 25%. G–I, The inflammatory response, as shown by activated glia (Iba1 stain), was also halved. J–L, Mice treated with liraglutide also had a significant increase in young neurons (doublecortin-positive cells) compared with saline-treated animals. Sample micrographs show saline-treated (top), liraglutide-treated (middle), and overall (bottom) quantification. ***p < 0.001 (Student's t test), n = 6).
Figure 5.
Figure 5.
Synaptophysin levels are partially restored by liraglutide treatment in APP/PS1 mice. A–D, Representative hippocampal images of synaptophysin-stained brains of both wild-type (A, B) and APP/PS1 (C, D) mice are shown. E–J, Quantification of levels of expression of synaptophysin demonstrates that wild-type liraglutide- and saline-treated animals had significantly higher expression levels in all hippocampal regions analyzed than both saline- and liraglutide-treated APP/PS1 mice (one-way ANOVA, p < 0.01 and p < 0.001). Liraglutide treatment had no effect on synaptophysin levels in wild-type mice, but increased hippocampal synaptophysin levels in APP/PS1 mice, to varying degrees, in all regions (one-way ANOVA, p < 0.05 and p < 0.001), when compared with saline-treated APP/PS1 mice. K, L, Liraglutide treatment also increased synaptophysin levels in the interior (K), but not the exterior (L) cortex in liraglutide-treated APP/PS1 mice versus APP/PS1 saline controls. Synaptophysin levels in both exterior and interior cortex were much higher in wild-type mice than in APP/PS1 animals (p < 0.0001); however, liraglutide treatment did not change synaptophysin expression in liraglutide-treated wild-type versus saline-treated wild-type mice. *p < 0.05, **p < 0.01, ***p < 0.001, n = 6 per group.
Figure 6.
Figure 6.
Soluble Aβ oligomer and APP levels are reduced in liraglutide-treated APP/PS1 mice. Oligomer β-amyloid levels and APP levels were measured by ELISA. Liraglutide significantly reduced both oligomer β-amyloid levels (A) (Student's t test, p = 0.0109) and brain APP levels (B) (Student's t test, p = 0.0272).
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