• Emilie Faivre and Christian Hölscher.
• School of Biomedical Sciences, Ulster University, Cromore road, Coleraine, BT52 1SA, UK.
• Alzheimers Res Ther. 2013 Jan 1;5(2):20.

IntroductionType 2 diabetes mellitus has been identified as a risk factor for Alzheimer's disease (AD). An impairment of insulin signaling as well as a desensitization of its receptor has been found in AD brains. Glucose-dependent insulinotropic polypeptide (GIP) normalises insulin signaling by facilitating insulin release. GIP directly modulates neurotransmitter release, LTP formation, and protects synapses from the detrimental effects of beta-amyloid fragments on LTP formation, and cell proliferation of progenitor cells in the dentate gyrus. Here we investigate the potential therapeutic property of the new long lasting incretin hormone analogue D-Ala(2)GIP on key symptoms found in a mouse model of Alzheimer' disease (APPswe/PS1detaE9).MethodsD-Ala(2)GIP was injected for 21 days at 25 nmol/kg ip once daily in APP/PS1 male mice and wild type (WT) littermates aged 6 or 12 months of age. Amyloid plaque load, inflammation biomarkers, synaptic plasticity in the brain (LTP), and memory were measured.ResultsD-Ala(2)GIP improved memory in WT mice and rescued the cognitive decline of 12 months old APP/PS1 mice in two different memory tasks. Furthermore, deterioration of synaptic function in the dentate gyrus and cortex was prevented in 12 months old APP/PS1 mice. D-Ala(2)GIP facilitated synaptic plasticity in APP/PS1 and WT mice and reduced the number of amyloid plaques in the cortex of D-Ala(2)GIP injected APP/PS1 mice. The inflammatory response in microglia was also reduced.ConclusionThe results demonstrate that D-Ala(2)GIP has neuroprotective properties on key hallmarks found in AD. This finding shows that novel GIP analogues have the potential as a novel therapeutic for AD.

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