title: Glucagon-like peptide-1 cleavage product GLP-1(9-36) amide rescues synaptic plasticity and memory deficits in Alzheimer's disease model mice.
abstract: Glucagon-like peptide-1 (GLP-1) is an endogenous intestinal peptide that enhances glucose-stimulated insulin secretion. Its natural cleavage product GLP-1(9-36)(amide) possesses distinct properties and does not affect insulin secretion. Here we report that pretreatment of hippocampal slices with GLP-1(9-36)(amide) prevented impaired long-term potentiation (LTP) and enhanced long-term depression induced by exogenous amyloid β peptide Aβ((1-42)). Similarly, hippocampal LTP impairments in amyloid precursor protein/presenilin 1 (APP/PS1) mutant mice that model Alzheimer's disease (AD) were prevented by GLP-1(9-36)(amide). In addition, treatment of APP/PS1 mice with GLP-1(9-36)(amide) at an age at which they display impaired spatial and contextual fear memory resulted in a reversal of their memory defects. At the molecular level, GLP-1(9-36)(amide) reduced elevated levels of mitochondrial-derived reactive oxygen species and restored dysregulated Akt-glycogen synthase kinase-3β signaling in the hippocampus of APP/PS1 mice. Our findings suggest that GLP-1(9-36)(amide) treatment may have therapeutic potential for AD and other diseases associated with cognitive dysfunction.
authors.affiliation: Center for Neural Science, New York University, New York, New York 10003, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Ma
authors.forename: Xueliang
authors.initials: X
authors.lastname: Du
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Pick
authors.forename: Guangzhi
authors.initials: G
authors.lastname: Sui
authors.forename: Michael
authors.initials: M
authors.lastname: Brownlee
authors.forename: Eric
authors.initials: E
authors.lastname: Klann
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D001245:Association Learning / Q000187:drug effects; D056654:CA3 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005239:Fear; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects*; D018697:Nootropic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D053764:Presenilin-1 / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D018697:Nootropic Agents; D009943:Organophosphorus Compounds; D010446:Peptide Fragments; D010455:Peptides; D053764:Presenilin-1; D017382:Reactive Oxygen Species; C075222:amyloid beta-protein (1-42); C114437:glucagon-like peptide-1 (9-36)-amide; D014451:Ubiquinone; C429014:mitoquinone; D052216:Glucagon-Like Peptide 1; C514862:Akt1 protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3