GLP-1 agonists facilitate hippocampal LTP and reverse the impairment of LTP induced by beta-amyloid.
Type 2 diabetes mellitus has been identified as a risk factor for Alzheimer's disease, and insulin signalling is often impaired in Alzheimer's disease, contributing to the neurodegenerative process. One potential strategy to help prevent this is the normalisation of insulin signalling in the brain. Therefore, the present study was designed to test the effects of the insulin-releasing gut hormone, glucagon-like peptide 1 (GLP-1). A protease-resistant form of GLP-1, (Val8)GLP-1, was also tested. Effects of both native GLP-1 and (Val8)GLP-1 on synaptic plasticity (LTP) in the hippocampus (15 nmol i.c.v.) were examined and results demonstrated for the first time that both peptides have enhancing effects on LTP. In sharp contrast, the inactive truncated form of GLP-1, GLP-1(9-36), had no effect on LTP. Injection of beta-amyloid (25-35) (100 nmol or 10 nmol i.c.v.), a peptide that aggregates in brains of Alzheimer's disease patients, impaired LTP. The injection of (Val8)GLP-1 (15 nmol i.c.v.) 30 min prior to injection of amyloid (25-35) (100 nmol i.c.v.) fully reversed the impairment of LTP induced by beta-amyloid. When (Val8)GLP-1 was administered 15 min prior to or simultaneously with beta-amyloid, no such reversal was observed. These results demonstrate for the first time that GLP-1 not only directly modulates neurotransmitter release and LTP formation, but also protects synapses from the detrimental effects of beta-amyloid fragments on LTP formation. Therefore, longer-acting GLP-1 agonists show great potential as a novel treatment for preventing neurodegenerative processes in neurodegenerative disorders.
Gault
Victor A
VA
School of Biomedical Sciences, University of Ulster, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, United Kingdom.
Hölscher
Christian
C
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000819:agonists* / Q000031:analogs & derivatives; D006624:Hippocampus / Q000187:drug effects*; D007276:Injections, Intraventricular; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000187:drug effects
D016229:Amyloid beta-Peptides; D052216:Glucagon-Like Peptide 1