Food for thought: Leptin regulation of hippocampal function and its role in Alzheimer's disease

Abstract

Accumulating evidence indicates that diet and body weight are important factors associated with Alzheimer's disease (AD), with a significant increase in AD risk linked to mid-life obesity, and weight loss frequently occurring in the early stages of AD. This has fuelled interest in the hormone leptin, as it is an important hypothalamic regulator of food intake and body weight, but leptin also markedly influences the functioning of the hippocampus; a key brain region that degenerates in AD. Increasing evidence indicates that leptin has cognitive enhancing properties as it facilitates the cellular events that underlie hippocampal-dependent learning and memory. However, significant reductions in leptin's capacity to regulate hippocampal synaptic function occurs with age and dysfunctions in the leptin system are associated with an increased risk of AD. Moreover, leptin is a potential novel target in AD as leptin treatment has beneficial effects in various models of AD. Here we summarise recent advances in leptin neurobiology with particular focus on regulation of hippocampal synaptic function by leptin and the implications of this for neurodegenerative disorders like AD. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.'

Role of sex and high fat diet in metabolic and hypothalamic disturbances in the 3xTg-AD mouse model of Alzheimer’s disease

“…Leptin has been explicitly shown to play a role in maintaining proper structure and function of the hippocampus [102] and is protective against Aβ and tau pathology [27]. Taken together, these findings support a growing body of evidence that normalizing metabolic dysfunction and perhaps specifically leptin signaling could prove to be a novel target for treatment of AD [31].…”

“…Hormones involved in the regulation of energy balance have also been shown to specifically affect amyloid processing, tau, and inflammation [25][26][27][28][29][30]. Additionally, glucose levels, as well as leptin and insulin signaling, not only play a role in maintaining metabolic homeostasis but are also vital to maintaining hippocampal function and supporting cognitive processes [31][32][33][34]. Therefore, interventions targeting metabolic and hypothalamic dysfunction may also contribute to improved outcomes in AD.…”

Pathways of Prevention: A Scoping Review of Dietary and Exercise Interventions for Neurocognition

“…Similar associations have been observed for HTN, with prospective studies demonstrating that the presence of HTN in midlife is associated with more than double the risk of neurocognitive decline [303][304][305] and dementia, [305][306][307][308][309] and may have particularly deleterious effects in the presence of obesity [310,311]. As reviewed in detail elsewhere, impaired peripheral metabolic function likely impairs central metabolic function over time through insulin and leptin resistance, [ 50,312] resulting in blunted CNS metabolic responses, energy exchange, and lipid metabolism.…”

Cell proliferation and neurogenesis alterations in Alzheimer’s disease and diabetes mellitus mixed murine models

“…At this point, it should also be noted that db/db mice are functional KO for the leptin receptor and it is possible that the observed alterations are not exclusively related to the diabetic process. The db/db mouse is a widely used model of T2D and metabolic syndrome, but leptin signaling is involved in regulating neural plasticity, synaptic function, glutamate receptor trafficking, neuronal morphology, microglial function or cognition (McGregor & Harvey, 2017; Paz‐Filho, 2016). Previous studies have shown that leptin administration may increase cell proliferation in the mouse DG without affecting cell differentiation and survival (Garza et al, 2008), and that leptin may stimulate the proliferation of neuronal precursors in APP/PS1 mice (Perez‐Gonzalez et al, 2011).…”

“…We studied APP/PS1xdb/db mice at three different time points: at 4 weeks of age, when the diabetic process and amyloid deposition have not yet commenced; at 14 weeks of age, when T2D has started but amyloid deposition has not occurred; and at 26 weeks of age, when T2D and AD have significantly progressed, as observed in the clinic. The db/db mouse lacks the leptin receptor, and leptin is known to be involved in synaptic and microglial function (McGregor & Harvey, 2017; Paz‐Filho, 2016) and cell proliferation (Garza, Guo, Zhang, & Lu, 2008).…”