The Neuronal Actions of Leptin and the Implications for Treating Alzheimer's Disease.

Jenni Harvey,Kirsty Hamilton

doi:10.3390/ph14010052

Jenni Harvey, Kirsty Hamilton

Open Access

https://doi.org/10.3390/ph14010052

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Abstract

It is widely accepted that the endocrine hormone leptin controls food intake and energy homeostasis via activation of leptin receptors expressed on hypothalamic arcuate neurons. The hippocampal formation also displays raised levels of leptin receptor expression and accumulating evidence indicates that leptin has a significant impact on hippocampal synaptic function. Thus, cellular and behavioural studies support a cognitive enhancing role for leptin as excitatory synaptic transmission, synaptic plasticity and glutamate receptor trafficking at hippocampal Schaffer collateral (SC)-CA1 synapses are regulated by leptin, and treatment with leptin enhances performance in hippocampus-dependent memory tasks. Recent studies indicate that hippocampal temporoammonic (TA)-CA1 synapses are also a key target for leptin. The ability of leptin to regulate TA-CA1 synapses has important functional consequences as TA-CA1 synapses are implicated in spatial and episodic memory processes. Moreover, degeneration is initiated in the TA pathway at very early stages of Alzheimer’s disease, and recent clinical evidence has revealed links between plasma leptin levels and the incidence of Alzheimer’s disease (AD). Additionally, accumulating evidence indicates that leptin has neuroprotective actions in various AD models, whereas dysfunctions in the leptin system accelerate AD pathogenesis. Here, we review the data implicating the leptin system as a potential novel target for AD, and the evidence that boosting the hippocampal actions of leptin may be beneficial.

Highlights

As NMDA receptor activation is a pre-requisite for leptin-induced long-term potentiation (LTP), and it is known that NMDA receptor function declines with age, it is feasible that a decrease in the ability of leptin to enhance NMDA receptor function contributes to the attenuated leptin-responsiveness with age, this remains to be determined experimentally
The neuronal actions of the metabolic hormone leptin are known to extend beyond the hypothalamus and energy homeostasis, to the hippocampal formation where leptin boosts cognitive function
In addition to regulating classical Schaffer collateral (SC)-CA1 synapses that play a role in spatial memory, TA-CA1 synapses have been identified as an important target for leptin

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. It is over 50 years since Hervey performed ground-breaking parabiosis experiments which suggested that a circulatory factor regulates food intake and body weight [1]. After periods of starvation or fasting, the circulating leptin levels fall, which acts as a stimulus for feeding [5]. Studies in this area have been aided by the availability of rodents with naturally occurring mutations in the leptin and lepR genes. The low incidence of leptin-specific mutations in humans indicates that genetic abnormalities in the leptin system are not the principal route for the development of obesity in humans

Leptin Receptor Isoforms

Leptin Receptor-Driven Signalling

Leptin Receptor Expression in the CNS

SC-CA1 Synapses

TA-CA1 Synapses

Leptin Regulation of AMPA Receptor Trafficking

Neuroprotective Actions of Leptin

Leptin Prevents Aβ-Driven Impairments at Hippocampal Synapses

Leptin Improves Hippocampus-Dependent Learning and Memory

Targeting the Leptin System as a Novel Therapeutic in AD?

Protective Actions of Leptin in Other Neurodegenerative Diseases

Findings