Type 2 diabetes has been identified as a risk factor for Alzheimer's disease (AD). Insulin signalling is often impaired in AD, contributing to the neurodegeneration observed in AD patients. One potential strategy to overcome this impairment is to normalise insulin signalling in the brain. In the present study, we have examined the effects of an enzyme-resistant analogue of glucose-dependent insulinotropic polypeptide (GIP), N-AcGIP, on synaptic plasticity. N-AcGIP is stable, long-acting peptide hormone that regulates glucose homeostasis and insulin release. We tested the effects of native GIP and the agonist N-AcGIP on synaptic plasticity (LTP) in the hippocampus (15nmol icv.) and report for the first time that both peptides have enhancing effects on LTP. In contrast, the antagonist of GIP, Pro(3)GIP (15nmol icv.), reduced LTP. Injection of beta-amyloid(25-35) (100nmol), a peptide that aggregates in brains of AD patients, also impaired LTP. The injection of N-AcGIP (15nmol icv.) 30 min prior to injection of amyloid(25-35) (100nmol icv.) fully reversed the impairment of LTP induced by beta-amyloid. The results demonstrate for the first time that GIP and particularly enzyme-resistant forms not only directly modulates neurotransmitter release and LTP formation, but also protect synapses from the detrimental effects of beta-amyloid fragments on LTP formation. The use of enzyme-resistant analogues of GIP show great promise as a potential novel treatment for preventing neurodegenerative processes in AD and other related disorders.