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

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.

Leptin—A Potential Bridge between Fat Metabolism and the Brain’s Vulnerability to Neuropsychiatric Disorders: A Systematic Review

“…The identification of the central actions of leptin when signaling through its specific LepRls in the neurons of the neuroendocrine and hippocampal circuits elucidates a complex and integrated central control of body energy (expenditure vs. storage) and sophisticated self-defense of the brain, thus shedding light on how it modulates satiety and compulsion [ 30 ].…”

“…The fine-tuning of leptin-LepRls signaling, which can be affected by either too-low or too-high leptin concentrations, appears to be crucial to ensure healthy eating behaviors [ 25 , 26 , 27 , 28 ]. Regulation of LepRls might be the linking factor enhancing the influence of weight control on the development of psychiatric disorders [ 29 , 30 , 31 ].…”

Aging affects cognition and hippocampal ultrastructure in male Wistar rats

“…Similarly, the aged rats travelled significantly larger distance to reach the platform in the MWM compared to the other age groups. Aged rats also exhibited ultrastructural changes in the CA1 region of the hippocampus, an area intimately involved in cognitive functions (Hamilton & Harvey, 2021; Scheff et al., 2007). Hence, among various measured parameters, it was found that the total number of presynaptic vesicles as well as total number of vesicles in the resting pool were significantly lower in aged rats compared to the other two age groups.…”

“…Recently, using behavioral and electron microscopic (EM) approaches, we saw manifestation of anxiety‐like behavior and concomitant alterations in ultrastructure of the central nucleus of amygdala, a brain region that plays a key role in emotional regulation in aged rats (Lomidze et al., 2020). Applying the same approach in the present study, we evaluated the cognitive function of aged rats in comparison to both adolescent and adult rats as well as the ultrastructure changes in CA1 region of the hippocampus, an area intimately involved in cognitive functions (Hamilton & Harvey, 2021; Scheff et al., 2007).…”

Activity of Selected Group of Monoterpenes in Alzheimer’s Disease Symptoms in Experimental Model Studies—A Non-Systematic Review

“…They also regulate pro-inflammatory cytokines, such as NF-κB, thus playing a key role in the AD pathogenesis. Leptin, however, appears to partially regulate monoterpenoid neuroprotection and cognition immune responses [ 94 , 95 , 96 ].…”