D-Ala 2 GIP Facilitated Synaptic Plasticity and Reduces Plaque Load in Aged Wild Type Mice and in an Alzheimer's Disease Mouse Model

Type 2 diabetes mellitus has been identified as a risk factor for Alzheimer's disease (AD). We have previously shown that glucose-dependent insulinotropic polypeptide (GIP) analogues that originally have been developed to treat diabetes have neuroprotective effects in the brains of the APPswe/PS1ΔE9 mouse model of AD. In a previous study, the analogue D-Ala²GIP intraperitoneally (i.p.) in 12 months old animals, an age that represents early phase AD, D-Ala²GIP improved memory in wild type (WT) mice and rescued the cognitive decline of 12 months old AβPP/PS1 mice. Synapse numbers and synaptic plasticity was also protected. Importantly, the amyloid plaque load in the cortex was reduced. In the present study, we tested D-Ala²GIP in 19 months old AβPP/PS1 mice or littermate controls to find out if the drug may have protective effects even at an advanced stage of AD. Mice were injected for 21 days at 25 nmol/kg i.p. once daily. Interestingly, the age-related reduction of synaptic numbers in the DG and cortex was prevented in WT control mice. D-Ala²GIP facilitated synaptic plasticity in AβPP/PS1 and WT mice and reduced the number of amyloid plaques and activated microglia in the cortex of AβPP/PS1 mice. The results show that D-Ala²GIP not only has protective but also regenerative properties in the brain of aged WT mice, and on key biomarkers found in AD in AβPP/PS1 mice. This suggests that novel GIP analogues may have beneficial effects in non-demented aged people and perhaps even in AD patients even when the disease is further progressed.