Leptin signaling and Alzheimer's disease

Am J Neurodegener Dis. 2012;1(3):245-65. Epub 2012 Nov 18.


Leptin, an adipocytokine produced in the peripheral system as well as in the brain, is implicated in obesity, food intake, glucose homeostasis, and energy expenditure. Leptin expression levels and signaling pathways may also be linked to the pathophysiology of neurodegenerative diseases including Alzheimer's disease. Epidemiological studies have demonstrated that higher circulating leptin levels are associated with lower risk of dementia including Alzheimer's disease, and lower circulating levels of leptin have been reported in patients with Alzheimer's disease. Leptin receptors are highly expressed in the hippocampus, a brain area involved in learning and memory and severely affected during the course of Alzheimer's disease. In laboratory studies, several in vivo and in vitro studies have shown that leptin supplementation decreases amyloid-β (Aβ) production and tau phosphorylation, two major biochemical events that play a key role in the pathogenesis of Alzheimer's disease. In this review, we will review the structure of leptin, the type of receptors of leptin in the brain, the various biological functions attributed to this adipocytokine, the signaling pathways that govern leptin actions, and the potential role of leptin in the pathophysiology of Alzheimer's disease. Leptin exerts its functions by binding to the leptin receptor (ObR). This binding can involve several signaling pathways including JAK/STAT pathway, ERK pathway and the PI3K/Akt/mTOR Pathway. Modulation of these pathways leads to the regulation of a multitude of functions that define the intricate involvement of leptin in various physiological tasks. In this review, we will specifically relate the potential involvement of leptin signaling in Alzheimer's disease based on work published by several laboratories including ours. All this work points to leptin as a possible target for developing supplementation therapies for reducing the progression of Alzheimer's disease.

Keywords: Abeta; Alzheimer’s disease; BACE1; ERK; JAK/STAT pathway; PI3K/AKT/mTOR pathway; SIRT; hippocampus; hypothalamus; leptin; leptin receptors.