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

Gayle Helane Doherty, D Beccano-Kelly, SD Yan, Frank J Gunn-Moore, J Harvey

Research output: Contribution to journalArticlepeer-review

99 Citations (Scopus)

Abstract

Accumulation of amyloid-β (Aβ1-42) 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 Aβ1-42on hippocampal long-term potentiation (LTP). Moreover leptin inhibits Aβ1-42-driven facilitation of long-term depression (LTD) and internalization of the AMPA receptor subunit, GluR1, via activation of PI3-kinase. Leptin also protects cortical neurons from Aβ1-42-induced cell deathby a STAT-3-dependent mechanism. Furthermore, leptin inhibits Aβ1-42-mediated upregulation of endophilin I and phosphorylated tau (p-tau) in vitro, whereas cortical levels of endophilin I and p-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 languageEnglish
Pages (from-to)226-237
JournalNeurobiology of Aging
Volume34
Issue number1
Early online date24 Aug 2012
DOIs
Publication statusPublished - Jan 2013

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