1. Leptin prevents hippocampal synaptic disruption and neuronal cell death induced by amyloid β.
- Author
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Doherty GH, Beccano-Kelly D, Yan SD, Gunn-Moore FJ, and Harvey J
- Subjects
- Analysis of Variance, Animals, Animals, Newborn, Biophysics, Cell Death drug effects, Cells, Cultured, Cerebral Cortex cytology, Dose-Response Relationship, Drug, Drug Interactions, Electric Stimulation, Embryo, Mammalian, Enzyme Inhibitors pharmacology, Gene Expression Regulation drug effects, Mice, Mitogen-Activated Protein Kinase 1 metabolism, Organ Culture Techniques, Patch-Clamp Techniques, Rats, Receptors, AMPA metabolism, STAT3 Transcription Factor metabolism, Signal Transduction drug effects, Synaptic Potentials drug effects, Tetrazolium Salts, Thiazoles, tau Proteins metabolism, Amyloid beta-Peptides pharmacology, Hippocampus cytology, Leptin pharmacology, Neurons drug effects, Neuroprotective Agents pharmacology, Peptide Fragments pharmacology, Synapses drug effects
- 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., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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