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Am J Neurodegener Dis 2012;1(3):245-265

Original Article
Leptin signaling and Alzheimer’s disease

Gurdeep Marwarha, Othman Ghribi

Department of Pharmacology, Physiology and Therapeutics, University of North Dakota, School of Medicine and Health
Sciences, Grand Forks, ND 58202, USA

Received October 12, 2012; Accepted November 9, 2012; Epub November 18, 2012; Published November 30, 2012

Abstract: 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. (AJND1210004).

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


Address all correspondence to:
Dr. Othman Ghribi
Department of Pharmacology, Physiology and Therapeutics
University of North Dakota School of Medicine and Health Sciences
501 North Columbia Road, Grand Forks, ND 58202, USA.
Tel: 701 777 2522; Fax: 701 777 4490
E-mail: othman.ghribi@med.und.edu