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, contri...

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Published in:Journal of neurophysiology 2008-04, Vol.99 (4), p.1590-1595
Main Authors: Gault, Victor A, Holscher, Christian
Format: Article
Language:English
Subjects:
Amyloid beta-Peptides - antagonists & inhibitors
Amyloid beta-Peptides - pharmacology
Animals
Electric Stimulation
Excitatory Postsynaptic Potentials - drug effects
Gastric Inhibitory Polypeptide - agonists
Gastric Inhibitory Polypeptide - analogs & derivatives
Gastric Inhibitory Polypeptide - pharmacology
Hippocampus - drug effects
Injections, Intraventricular
Long-Term Potentiation - drug effects
Male
Peptide Fragments - antagonists & inhibitors
Peptide Fragments - pharmacology
Peptide Hydrolases - chemistry
Rats
Rats, Wistar
Synapses - drug effects
Synapses - physiology
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Summary: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. Address for reprint requests and other correspondence: C. Hölscher, University of Ulster, Cromore Road, Coleraine, BT52 1SA, Northern Ireland (E-mail: c.holscher{at}ulster.ac.uk )
ISSN:0022-3077
1522-1598
DOI:10.1152/jn.01161.2007