Leptin prevents hippocampal synaptic disruption and neuronal cell death induced by amyloid β

• Published in: Neurobiology of aging 2013, Vol.34 (1), p.226-237
• Main Authors: Doherty, Gayle H, Beccano-Kelly, Dayne, Yan, Shi Du, Gunn-Moore, Frank J, Harvey, Jenni
• Format: Article
• Language: English
• Subjects: AMPA receptor trafficking; Amyloid beta; Amyloid beta-Peptides - pharmacology; 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; Endophilin I; Enzyme Inhibitors - pharmacology; Gene Expression Regulation - drug effects; Hippocampus - cytology; Internal Medicine; Leptin; Leptin - pharmacology; Mice; Mitogen-Activated Protein Kinase 1 - metabolism; Neurology; Neurons - drug effects; Neuroprotective Agents - pharmacology; Organ Culture Techniques; Patch-Clamp Techniques; Peptide Fragments - pharmacology; Rats; Receptors, AMPA - metabolism; Signal Transduction - drug effects; STAT3 Transcription Factor - metabolism; Synapses - drug effects; Synaptic plasticity; Synaptic Potentials - drug effects; tau Proteins - metabolism; Tetrazolium Salts; Thiazoles
• ISSN: 0197-4580; 1558-1497; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2012.08.003

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 Aβ1–42 on hippocampal long-term potentiation. Moreover leptin inhibits Aβ1–42 -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 Aβ1–42 -induced cell death by a signal transducer and activator of transcription-3 (STAT-3)-dependent mechanism. Furthermore, leptin inhibits Aβ1–42 -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.