title: Leptin prevents hippocampal synaptic disruption and neuronal cell death induced by amyloid β.
abstract: Accumulation of amyloid-β (Aβ) is a key event mediating the cognitive deficits in Alzheimer's disease (AD) as Aβ promotes synaptic dysfunction and triggers neuronal death. Recent evidence has linked the hormone leptin to AD as leptin levels are markedly attenuated in AD patients. Leptin is also a potential cognitive enhancer as it facilitates the cellular events underlying hippocampal learning and memory. Here we show that leptin prevents the detrimental effects of Aβ(1-42) on hippocampal long-term potentiation. Moreover leptin inhibits Aβ(1-42)-driven facilitation of long-term depression and internalization of the 2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl)propanoic acid (AMPA) receptor subunit, GluR1, via activation of PI3-kinase. Leptin also protects cortical neurons from Aβ(1-42)-induced cell death by a signal transducer and activator of transcription-3 (STAT-3)-dependent mechanism. Furthermore, leptin inhibits Aβ(1-42)-mediated upregulation of endophilin I and phosphorylated tau in vitro, whereas cortical levels of endophilin I and phosphorylated tau are enhanced in leptin-insensitive Zucker fa/fa rats. Thus leptin benefits the functional characteristics and viability of neurons that degenerate in AD. These novel findings establish that the leptin system is an important therapeutic target in neurodegenerative conditions.
authors.affiliation: School of Biology, University of St. Andrews, St. Andrews, Fife, Scotland, UK.
authors.forename: Gayle H
authors.initials: GH
authors.lastname: Doherty
authors.forename: Dayne
authors.initials: D
authors.lastname: Beccano-Kelly
authors.forename: Shi Du
authors.initials: SD
authors.lastname: Yan
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gunn-Moore
authors.forename: Jenni
authors.initials: J
authors.lastname: Harvey
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001703:Biophysics; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology*; D020738:Leptin / Q000494:pharmacology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000187:drug effects*; D055366:Synaptic Potentials / Q000187:drug effects; D013778:Tetrazolium Salts; D013844:Thiazoles; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D020738:Leptin; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D018091:Receptors, AMPA; D050796:STAT3 Transcription Factor; D013778:Tetrazolium Salts; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D019950:Mitogen-Activated Protein Kinase 1; C022616:thiazolyl blue