Leptin attenuates the detrimental effects of β-amyloid on spatial memory and hippocampal later-phase long term potentiation in rats

Tong, Jia‐Qing; Zhang, Jun; Hao, Ming; Ju, Yang; Han, Yufei; Liu, Xiaojie; Shi, Hui; Wu, Mei‐Na; Liu, Qingsong; Qi, Jin-Shun

doi:10.1016/j.yhbeh.2015.06.013

Cited by 38 publications

(37 citation statements)

References 39 publications

(47 reference statements)

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“…This is the first time that leptin has been shown to enhance the specific type of memory that degrades in AD and the fact that this cognitive enhancement is also produced by leptin (116)(117)(118)(119)(120)(121)(122)(123)(124)(125)(126)(127)(128)(129)(130) suggests that this fragment is a viable tool to treat memory dysfunction caused by damage to the hippocampal-entorhinal network. Recent studies indicate that administration of leptin also protects against Aβ-induced impairments in spatial memory tasks (Tong et al 2015). Thus, it is feasible that administration of leptin (116-130) will also mirror the effects of leptin and protect against the chronic effects of Aβ on hippocampaldependent learning and memory.…”

Section: Discussionmentioning

confidence: 99%

“…In cellular models of AD, leptin treatment prevents the aberrant effects of Aβ, as leptin reverses the ability of Aβ to inhibit LTP and facilitate LTD in hippocampal slices (Doherty et al 2013) and it prevents Aβ-driven internalization of the AMPA receptor subunit, GluA1 in hippocampal neurons (Doherty et al 2013). Chronic intracerebroventricular injection of leptin also reverses Aβ-induced impairments in LTP in vivo (Tong et al 2015). In cell survival assays, leptin protects against Aβ-induced toxicity as neuronal viability is increased after leptin treatment.…”

Section: Q2mentioning

confidence: 99%

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A Leptin Fragment Mirrors the Cognitive Enhancing and Neuroprotective Actions of Leptin

et al. 2016

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A key pathology of Alzheimer's disease (AD) is amyloid β (Aβ) accumulation that triggers synaptic impairments and neuronal death. Metabolic disruption is common in AD and recent evidence implicates impaired leptin function in AD. Thus the leptin system may be a novel therapeutic target in AD. Indeed, leptin has cognitive enhancing properties and it prevents the aberrant effects of Aβ on hippocampal synaptic function and neuronal viability. However, as leptin is a large peptide, development of smaller leptin-mimetics may be the best therapeutic approach. Thus, we have examined the cognitive enhancing and neuroprotective properties of known bioactive leptin fragments. Here we show that the leptin (116-130) fragment, but not leptin (22-56), mirrored the ability of leptin to promote AMPA receptor trafficking to synapses and facilitate activity-dependent hippocampal synaptic plasticity. Administration of leptin (116-130) also mirrored the cognitive enhancing effects of leptin as it enhanced performance in episodic-like memory tests. Moreover, leptin (116-130) prevented hippocampal synaptic disruption and neuronal cell death in models of amyloid toxicity. These findings establish further the importance of the leptin system as a therapeutic target in AD.

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Section: Discussionmentioning

confidence: 99%

Section: Q2mentioning

confidence: 99%

A Leptin Fragment Mirrors the Cognitive Enhancing and Neuroprotective Actions of Leptin

et al. 2016

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“…Both exogenous leptin administration and leptin viral gene transfer led to improvements in behavior and memory tasks in transgenic mouse models of AD (Greco et al 2010; Pérez-González et al 2014). Furthermore, chronic intracerebroventricular leptin administration can also alleviate the Aβ 1–42-mediated spatial memory impairments and suppression of in vivo hippocampal late-phase LTP in rats (Tong et al 2015). In contrast, leptin deficiency can worsen brain amyloid burden and cognitive function as demonstrated when transgenic mice overexpressing APP were crossed to leptin deficient ob/ob mice (Takeda et al 2010).…”

Section: Leptin and Alzheimer’s Disease: Cellular And Animal Modelsmentioning

confidence: 99%

Leptin Dysfunction and Alzheimer’s Disease: Evidence from Cellular, Animal, and Human Studies

McGuire

Ishii

2016

Cell Mol Neurobiol

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There is accumulating evidence from epidemiological studies that changes in body weight are associated with Alzheimer’s disease (AD) from mid-life obesity increasing the risk of developing AD to weight loss occurring at the earliest stages of AD. Therefore, factors that regulate body weight are likely to influence the development and progression of AD. The adipocyte-derived hormone leptin has emerged as a major regulator of body weight mainly by activating hypothalamic neural circuits. Leptin also has several pleotropic effects including regulating cognitive function and having neuroprotective effects, suggesting a potential link between leptin and AD. Here, we will examine the relationship between leptin and AD by reviewing the recent evidence from cellular and animal models to human studies. We present a model where leptin has a bidirectional role in AD. Not only can alterations in leptin levels and function worsen cognitive decline and progression of AD pathology, but AD pathology, in of itself, can disrupt leptin signaling, which together would lead to a downward spiral of progressive neurodegeneration and worsening body weight and systemic metabolic deficits. Collectively, these studies serve as a framework to highlight the importance of understanding the molecular mechanisms underlying the body weight and systemic metabolic deficits in AD, which has the potential to open new avenues that may ultimately lead to novel therapeutic targets and diagnostic tools.

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“…For example, it has been shown that longterm leptin administration increases neurogenesis in adult mice [Garza et al, 2008[Garza et al, , 2012 and that leptin signaling leads to synaptogenesis and dendritic morphogenesis in the hippocampus via mitogen-activated protein kinase and cAMP-response element-binding protein pathways [Dhar et al, 2014;O'Malley et al, 2007]. Animal models for AD also showed that leptin can improve tau pathology [Greco et al, 2008], amyloid-beta clearance [Fewlass et al, 2004], and related deficits in long-term potentiation and memory [Tong et al, 2015]. However note that a recent study reported a negative correlation of leptin with Aß, measured in the CSF of female AD patients, which was discussed to contribute to the higher risk of developing AD in women [Diehl-Wiesenecker et al, 2015].…”

Section: Underlying Mechanismsmentioning

confidence: 99%

Impact of leptin on memory function and hippocampal structure in mild cognitive impairment

Witte

Köbe

Graunke

et al. 2016

Human Brain Mapping

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Metabolic changes have been suggested to contribute to dementia and its precursor mild cognitive impairment (MCI), yet previous results particularly for the "satiety hormone" leptin are mixed. Therefore, we aimed to determine if MCI patients show systematic differences in leptin, independent of sex, adipose mass, age, and glucose and lipid metabolism, and whether leptin levels correlated with memory performance and hippocampal integrity. Forty MCI patients (20 females, aged 67 years ± 7 SD) were compared to 40 healthy controls (HC) that were pair-wise matched for sex, age, and body fat. Memory performance was assessed using the auditory verbal learning test. Volume and microstructure of the hippocampus were determined using 3T-neuroimaging. Fasting serum markers of leptin, glucose and lipid metabolism, and other confounding factors were assayed. MCI patients, compared with HC, showed lower serum leptin, independent of sex, age, and body fat (P < 0.001). Glucose and lipid markers did not attenuate these results. Moreover, MCI patients exhibited poorer memory and lower volume and microstructural integrity within hippocampal subfields. While leptin and memory were not significantly correlated, mediation analyses indicated that lower leptin contributed to poorer memory through its negative effect on right hippocampus volume and left hippocampus microstructure. We demonstrated that MCI is associated with lower serum leptin independent of sex, age, body fat, glucose, and lipid metabolism. Our data further suggest that inefficient leptin signaling could partly contribute to decreases in memory performance through changes in hippocampus structure, a hypothesis that should now be verified in longitudinal studies. Hum Brain Mapp 37:4539-4549, 2016. © 2016 Wiley Periodicals, Inc.

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Leptin attenuates the detrimental effects of β-amyloid on spatial memory and hippocampal later-phase long term potentiation in rats

Cited by 38 publications

References 39 publications

A Leptin Fragment Mirrors the Cognitive Enhancing and Neuroprotective Actions of Leptin

A Leptin Fragment Mirrors the Cognitive Enhancing and Neuroprotective Actions of Leptin

Leptin Dysfunction and Alzheimer’s Disease: Evidence from Cellular, Animal, and Human Studies

Impact of leptin on memory function and hippocampal structure in mild cognitive impairment

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