Lixisenatide, a drug developed to treat type 2 diabetes, shows neuroprotective effects in a mouse model of Alzheimer's disease

Aug 10, 2014Neuropharmacology

Lixisenatide, a diabetes drug, may protect the brain in a mouse model of Alzheimer's disease

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Abstract

Both liraglutide and lixisenatide improved cognitive performance and synaptic plasticity in a mouse model of Alzheimer's disease.

Daily injections of liraglutide or lixisenatide enhanced performance in an object recognition task in APP/PS1 mice.
Both drugs significantly increased long-term potentiation (LTP) in the hippocampus of APP/PS1 mice.
Lixisenatide (1 nmol/kg) demonstrated the highest effectiveness among the doses tested.
The reduction of synapse numbers in APP/PS1 mice was prevented by both liraglutide and lixisenatide.
Both treatments reduced amyloid plaque load and chronic inflammation in the cortex of the mice.

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Type 2 diabetes is a risk factor for developing Alzheimer's disease (AD). In the brains of AD patients, insulin signalling is desensitised. The incretin hormone Glucagon-like peptide-1 (GLP-1) facilitates insulin signalling, and analogues such as liraglutide are on the market as treatments for type 2 diabetes. We have previously shown that liraglutide showed neuroprotective effects in the APPswe/PS1ΔE9 mouse model of AD. Here, we test the GLP-1 receptor agonist lixisenatide in the same mouse model and compare the effects to liraglutide. After ten weeks of daily i.p. injections with liraglutide (2.5 or 25 nmol/kg) or lixisenatide (1 or 10 nmol/kg) or saline of APP/PS1 mice at an age when amyloid plaques had already formed, performance in an object recognition task was improved in APP/PS1 mice by both drugs at all doses tested. When analysing synaptic plasticity in the hippocampus, LTP was strongly increased in APP/PS1 mice by either drug. Lixisenatide (1 nmol/kg) was most effective. The reduction of synapse numbers seen in APP/PS1 mice was prevented by the drugs. The amyloid plaque load and dense-core Congo red positive plaque load in the cortex was reduced by both drugs at all doses. The chronic inflammation response (microglial activation) was also reduced by all treatments. The results demonstrate that the GLP-1 receptor agonists liraglutide and lixisenatide which are on the market as treatments for type 2 diabetes show promise as potential drug treatments of AD. Lixisenatide was equally effective at a lower dose compared to liraglutide in some of the parameters measured.

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Lixisenatide, a drug developed to treat type 2 diabetes, shows neuroprotective effects in a mouse model of Alzheimer's disease

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