TY - JOUR

T1 - D-Ala2GIP facilitated synaptic plasticity and reduces plaque load in aged wild type mice and in an Alzheimer’s disease mouse model

AU - Faivre, Emilie

AU - Holscher, Christian

PY - 2013/4/8

Y1 - 2013/4/8

N2 - 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.

AB - 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.

KW - Growth factor

KW - incretins

KW - insulin

KW - neuroprotection

U2 - 10.3233/JAD-121888

DO - 10.3233/JAD-121888

M3 - Journal article

VL - 35

SP - 267

EP - 283

JO - Journal of Alzheimer's Disease

JF - Journal of Alzheimer's Disease

SN - 1387-2877

IS - 2

ER -