Type 2 diabetes mellitus has been identified as a risk factor for Alzheimer's disease (AD). Insulin is a neuroprotective growth factor, and an impairment of insulin signalling has been found in AD brains. Glucose-dependent insulinotropic polypeptide (GIP), an incretin hormone, normalises insulin signalling and also acts as a neuroprotective growth factor. GIP plays an important role in memory formation, synaptic plasticity and cell proliferation. We have shown previously that the long-lasting incretin hormone analogue D-Ala(2)GIP protects memory formation and synaptic plasticity, reduces plaques, normalises the proliferation of stem cells, reduces the activation of microglia, and prevents the loss of synapses in the cortex of the APPswe/PS1deltaE9 mouse model of Alzheimer's disease. D-Ala(2)GIP was injected for 35 days at 25 nmol/kg i.p. once daily in APP/PS1 male mice and wild-type (WT) littermates aged 6, 12 and 19 months. In a follow-up study, we analysed plaque load, the activation of astrocytes as a means of chronic inflammation in the brain, and oxidative stress in the brains of these mice (8-oxoguanine levels). D-Ala(2)GIP reduced the amyloid plaque load in 12- and 19-month-old mice, and the inflammation response as shown in the reduction of activated astrocytes in 12- and 19-month old APP/PS1 mice. Chronic oxidative stress in the brain was reduced in 12- and 19-month-old mice as shown in the reduction of 8-oxoguanine levels in the cortex of D-Ala(2)GIP-injected APP/PS1 mice. The results demonstrate that D-Ala(2)GIP has neuroprotective properties on key markers found in Alzheimer's disease. This finding shows that novel GIP analogues have the potential to be developed as novel therapeutics for Alzheimer's disease.
