Regular articleLeptin prevents hippocampal synaptic disruption and neuronal cell death induced by amyloid β
Introduction
Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by accumulation of extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles containing hyperphosphorylated tau. Abnormal proteolytic processing of amyloid precursor protein (APP), leading to generation of Aβ peptides, is central to AD pathogenesis with Aβ1–42 toxicity linked to synaptic aberration and neuronal death. Soluble Aβ oligomers cause rapid, detrimental effects on excitatory synaptic function (Cerpa et al., 2008, Hsieh et al., 2006) leading to impaired learning and memory (Billings et al., 2007). Hippocampal long-term potentiation (LTP) and long-term depression (LTD) are cellular correlates of learning and memory and oligomeric Aβ is reported to inhibit LTP (Shankar et al., 2008, Walsh et al., 2002) and enhance LTD (Hsieh et al., 2006, Li et al., 2009). 2-Amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl)propanoic acid (AMPA) receptor trafficking is also pivotal for hippocampal synaptic plasticity and Aβ promotes synaptic dysfunction by altering glutamate receptor trafficking processes (Hsieh et al., 2006, Liu et al., 2010). In addition Aβ enhances tau phosphorylation (Greenberg et al., 1994), a critical process in the development of neurofibrillary tangles, and it induces neuronal death (Barger et al., 1995), thereby contributing to the neuronal loss observed in AD. Changes in the expression of synaptic proteins, such as endophilin I, also closely correlate with the progression of AD (Ren et al., 2008). However, the cellular processes responsible for altering the expression of endophilin I in AD are unclear.
Diet and lifestyle are key factors influencing the risk of neurodegenerative disorders. It is well known that the hormone leptin regulates energy homeostasis via its actions in the hypothalamus (Spiegelman and Flier, 2001). However leptin receptors are expressed throughout the central nervous system and leptin influences many neuronal functions (Harvey, 2007). Recent studies indicate that leptin-insensitivity causes deficits in hippocampal synaptic plasticity and spatial memory (Li et al., 2002, Stranahan et al., 2008), whereas memory is enhanced following administration of leptin (Wayner et al., 2004). Moreover, leptin regulates diverse aspects of hippocampal synaptic function including neuronal morphology, synaptic plasticity and glutamate receptor trafficking (Moult et al., 2009, Moult et al., 2010, O'Malley et al., 2007, Shanley et al., 2001). Reductions in hippocampal dendritic spine density have also been reported in leptin-insensitive db/db mice (Stranahan et al., 2009). Leptin also has protective actions both in the periphery (Saxena et al., 2004) and in neuronal cells (Russo et al., 2004). Indeed, leptin protects hippocampal neurons from apoptosis (Guo et al., 2008), and enhances the survival of cerebellar Purkinje cells (Oldreive et al., 2008) and dopaminergic neurons in Parkinson's disease models (Doherty et al., 2008, Weng et al., 2007). Thus, leptin may also inhibit cell death associated with AD.
Clinical studies have linked leptin to AD as circulating leptin levels are markedly lower in AD patients (Power et al., 2001). A recent prospective study has also identified that low leptin levels correlate with an increased incidence of AD (Lieb et al., 2009). In addition, rodents with familial AD mutations have low circulating leptin levels and leptin reduces Aβ levels in these models (Fewlass et al., 2004). Leptin also improves memory in a model of Aβ-induced toxicity (Farr et al., 2006) and reduces tau phosphorylation in neuronal cell lines (Greco et al., 2009).
It is well established that pathological assemblies of Aβ oligomers detrimentally affect excitatory synaptic function (Shankar et al., 2008, Walsh et al., 2002). Here we show for the first time that the hormone leptin reversed the inhibition of hippocampal LTP by Aβ1–42. In addition, leptin attenuated Aβ1–42-driven facilitation of LTD and AMPA receptor removal from hippocampal synapses via activation of PI3-kinase. Leptin also protected cortical neurons from Aβ1–42-induced toxicity via STAT-3 and it prevented Aβ-dependent upregulation of endophilin I and phosphorylated tau (p-tau). Moreover cortical levels of endophilin I and p-tau were significantly enhanced in Zucker fa/fa rats, indicating that key cellular pathways linked to AD pathogenesis are activated by leptin-insensitivity in vivo. These data indicate that leptin prevents the detrimental effects of Aβ on hippocampal synaptic function and neuronal viability and also reduces expression of 2 biomarkers linked to AD pathology. These findings establish that the leptin system is an important novel therapeutic target in AD.
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Preparation of Aβ
Aβ1–42 peptide was synthesized and purified by Dr. Elliott at Yale University (New Haven, CT, USA) based on the human Aβ sequence. The lyophilized powder was solubilized in dimethyl sulfoxide (DMSO) and diluted to a working concentration. For cell viability and biochemical assays Aβ was prepared as described previously as Aβ has shown to elicit toxicity when in a β sheet conformation (Simmons et al., 1994). Briefly, lypholized powder was solubilized in dH2O to a concentration of 1 mM in
Leptin reverses Aβ inhibition of hippocampal LTP
Previous studies indicate that Aβ1–42 inhibits hippocampal LTP (Li et al., 2009, Shankar et al., 2008). To determine if Aβ reproduces this effect, LTP was induced in control slices by HFS, which increased synaptic transmission to 169.4 ± 3.0% of baseline (n = 3; p < 0.01; Fig. 1A). HFS also induced LTP (171 ± 7.2% of baseline) in slices treated with the inactive peptide Aβ42–1 (1 μM; 40 minutes; n = 6; Fig. 1A). However, HFS failed to induce LTP in slices exposed to Aβ1–42 (1 μM; 109 ± 3.1% of
Discussion
Leptin regulates many hypothalamic functions, including energy balance (Spiegelman and Flier, 2001). However, there is extensive expression of leptin receptors in the central nervous system and evidence is accumulating that leptin has widespread central actions including significant cognitive enhancing effects (Moult et al., 2010, Shanley et al., 2001, Wayner et al., 2004). Several lines of evidence indicate that hippocampal synaptic plasticity is impaired in leptin-insensitive rodents (Li et
Disclosure statement
The authors report no actual or potential conflicts of interest.
All animals used in this study were housed and culled in accordance with Schedule 1 of UK Animals (Scientific Procedures) Act, 1986.
Acknowledgements
Dr. Doherty holds an Alzheimer's Society personal research fellowship (grant number 93) with support from the Henry Smith Charity. Alzheimer's Society is a charity (registration no. 296645) and a company registered in England and Wales (registration no. 2115499). J.H. is funded by The Cunningham Trust. F.G.M. is funded by both the Alzheimer's Research UK and Alzheimer's Society.
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The authors contributed equally to this study.