Abstract
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-Ala2GIP on key symptoms found in a mouse model of Alzheimer' disease (APPswe/PS1detaE9).MethodsD-Ala2GIP 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-Ala2GIP 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-Ala2GIP facilitated synaptic plasticity in APP/PS1 and WT mice and reduced the number of amyloid plaques in the cortex of D-Ala2GIP injected APP/PS1 mice. The inflammatory response in microglia was also reduced.ConclusionThe results demonstrate that D-Ala2GIP 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.
Highlights
Type 2 diabetes mellitus has been identified as a risk factor for Alzheimer’s disease (AD)
These statistics show that APP/PS1 mice had a higher body weight compared to wild type (WT) control mice, which was not influenced by the saline or D-Ala2GIP injection (Figure 2A)
No effect of interaction of groups and time was shown between the saline groups (F = 0.27, P > 0.05) or between the DAla2GIP groups (F = 0.05, P > 0.05). These statistics show that APP/PS1 mice had a higher body weight compared to WT control mice, and the D-Ala2GIP
Summary
Type 2 diabetes mellitus has been identified as a risk factor for Alzheimer’s disease (AD). There is evidence to suggest that beta-amyloid oligomers bind to insulin receptors in the brain and cause a reduction of insulin receptor expression on dendrites [18,19]. This impairment in insulin signaling leads to an impairment of neuronal function, plaque formation and may lead to formation of NFTs [20,21,22]. Insulin can regulate levels of phosphorylated tau and is a potent neuroprotective factor, which can increase neuronal survival and protect neurons against the toxicity of amyloid fragments [29,30]
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