Protease-resistant glucose-dependent insulinotropic polypeptide agonists facilitate hippocampal LTP and reverse the impairment of LTP induced by beta-amyloid.
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.
Gault
Victor A
VA
School of Biomedical Schiences, University of Ulster, Coleraine, Northern Ireland.
Hölscher
Christian
C
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D000818:Animals; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005749:Gastric Inhibitory Polypeptide / Q000819:agonists* / Q000031:analogs & derivatives* / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects*; D007276:Injections, Intraventricular; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D010447:Peptide Hydrolases / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / Q000187:drug effects / Q000502:physiology
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); D005749:Gastric Inhibitory Polypeptide; D010447:Peptide Hydrolases