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This Article Full Text Full Text (PDF) All Versions of this Article: 99/4/1590    most recent 01161.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Gault, V. A. Articles by Hölscher, C. Search for Related Content PubMed PubMed Citation Articles by Gault, V. A. Articles by Hölscher, C.

Protease-Resistant Glucose-Dependent Insulinotropic Polypeptide Agonists Facilitate Hippocampal LTP and Reverse the Impairment of LTP Induced by Beta-Amyloid

School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, United Kingdom

Submitted 20 October 2007; accepted in final form 28 January 2008

Type 2 diabetes has been identified as a risk factor for Alzheimer's disease (AD). Insulin signaling is often impaired in AD, contributing to the neurodegeneration observed in AD patients. One potential strategy to overcome this impairment is to normalize insulin signaling 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 a 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 [long-term potentiation (LTP)] in the hippocampus [15 nmol, administered intracerebroventricularly (icv)] and report for the first time that both peptides have enhancing effects on LTP. In contrast, the antagonist of GIP, Pro(3)GIP (15 nmol icv), reduced LTP. Injection of beta-amyloid(25–35) (100 nmol), a peptide that aggregates in brains of AD patients, also impaired LTP. The injection of N-AcGIP (15 nmol icv) 30 min prior to injection of amyloid(25–35) (100 nmol icv) fully reversed the impairment of LTP induced by beta-amyloid. The results demonstrate for the first time that GIP (particularly enzyme-resistant forms) not only directly modulates neurotransmitter release and LTP formation, but also protects 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.