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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.

Original publication

DOI

10.1016/j.neurobiolaging.2012.08.003

Type

Journal article

Journal

Neurobiol Aging

Publication Date

01/2013

Volume

34

Pages

226 - 237

Keywords

Amyloid beta-Peptides, Analysis of Variance, Animals, Animals, Newborn, Biophysics, Cell Death, Cells, Cultured, Cerebral Cortex, Dose-Response Relationship, Drug, Drug Interactions, Electric Stimulation, Embryo, Mammalian, Enzyme Inhibitors, Gene Expression Regulation, Hippocampus, Leptin, Mice, Mitogen-Activated Protein Kinase 1, Neurons, Neuroprotective Agents, Organ Culture Techniques, Patch-Clamp Techniques, Peptide Fragments, Rats, Receptors, AMPA, STAT3 Transcription Factor, Signal Transduction, Synapses, Synaptic Potentials, Tetrazolium Salts, Thiazoles, tau Proteins