title: Val⁸-GLP-1 remodels synaptic activity and intracellular calcium homeostasis impaired by amyloid β peptide in rats.
abstract: Type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer's disease (AD) in the elderly. Glucagon-like peptide-1 (GLP-1), a modulator in T2DM therapy, has been shown to have neuroprotective properties. However, the native GLP-1 can be rapidly degraded by the enzyme dipeptidyl peptidase IV (DPP IV); the neuroprotective mechanism of GLP-1 in the central nervous system is still an open question, and whether GLP-1 can prevent amyloid β (Aβ)-induced synaptic dysfunction and calcium disorder is still unclear. The present study, by using patch clamp and calcium imaging techniques, investigated the effects of Val⁸-GLP-1(7-36), a GLP-1 analogue with profound resistance to DPP IV, on the excitatory and inhibitory synaptic transmission and intracellular calcium concentration ([Ca²⁺](i) ) in the absence or presence of Aβ1-40. The results showed that 1) Aβ1-40 significantly reduced the frequency of miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) in CA1 pyramidal neurons of rat brain slices; 2) Val⁸-GLP-1(7-36) did not affect the activity of miniature postsynaptic currents but effectively protected against the Aβ1-40-induced decrease in mEPSC and mIPSC frequency; 3) Aβ1-40 significantly increased [Ca²⁺](i) in primary neuronal cultures; and 4) Val⁸-GLP-1(7-36) alone did not change the intracellular calcium level but prevented Aβ1-40-induced persistent elevation of [Ca²⁺](i). These findings demonstrate for the first time that central application of Val⁸-GLP-1(7-36) could protect against Aβ-induced synaptic dysfunction and intracellular calcium overloading, suggesting that the neuroprotection of GLP-1 may be involved in the remodeling of synaptic activity and intracellular calcium homeostasis in the brain.
authors: Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, China.
authors: Xiao-Hui
authors: XH
authors: Wang
authors: Wei
authors: W
authors: Yang
authors: Christian
authors: C
authors: Hölscher
authors: Zhao-Jun
authors: ZJ
authors: Wang
authors: Hong-Yan
authors: HY
authors: Cai
authors: Qing-Shan
authors: QS
authors: Li
authors: Jin-Shun
authors: JS
authors: Qi
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D006706:Homeostasis; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C555025:glucagon-like peptide 1 (7-36), Val(8)-; D052216:Glucagon-Like Peptide 1; D002118:Calcium