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Title: The role of glucose-dependent insulinotropic peptide signalling in the normal brain and therapeutic effects in an Alzheimer's disease mouse model
Author: Faivre, Emilie
Awarding Body: University of Ulster
Current Institution: Ulster University
Date of Award: 2011
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Alzheimer's disease (AD) is a neurodegenerative disease, characterized by cognitive impairments and occurrence of neuronal depositions of amyloid plaques. At present, no treatment for AD is known. A disturbance in insulin signaling and its receptor was recently highlighted in the brain of AD patients. In this study, the effect of glucose- dependent insulinotropic peptide (GIP) was investigated in the brain, as it is a potential candidate to activate a parallel signaling pathway to insulin. The lack of GIP receptor affects learning and memory in object recognition and Morris water maze tasks, synaptic plasticity and progenitor cell proliferation in the hippocampus of GIP receptor knockout mice. Effects of long-lasting GIP analogues were investigated on different physiological processes in the brain. D-Ala2GIP agonist at 25 nmol/kg seems to be the most effective dose after chronic administration in normal mice and no adverse side effects were observed. The antagonist (Pr03)GIP impaired memory formation after acute administration, while beneficial effects were observed on learning and synaptic plasticity following chronic application. The potential beneficial effects of D-Ala2GIP treatment on AD pathology were tested in mouse model of AD (APPIPS 1 mice) aged 6, 12 and 19 months old and wild-type age matched mice, that were injected daily with D-Ala2GIP for 21 days. This treatment preserved synaptic function of 12 month-old APP/PSl mice and old WT mice, leading to improvement of long-term potentiation and learning and memory, and protects synapses against degeneration. D-Ala2GIP reduced the number of plaques and inflammation in the cortex of APP /PS 1 mice. The beneficial action of GIP was potentiated by a longer and earlier treatment. In both 6 month-old and 11 month-old APPIPSI mice, daily treatment for 14 week and 34 week, respectively, D-Ala2GIP prevented synapse loss and reduced the number of plaque load and inflammation in the brain. These results suggest that GIP analogues may be an attractive therapeutic approach for the treatment of neurodegenerative diseases.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available