Leptin: A Novel Therapeutic Strategy for Alzheimer's Disease

Issue title: Oxidative Stress, Reactive Metabolites, Inflammation, and RAGE – Building a Bridge from Alzheimer's Disease to Diabetes and Vice Versa

Guest editors: Angelika Bierhaus

Article type: Research Article

Authors: Tezapsidis, Nikolaos^{a; *} | Johnston, Jane M.^a | Smith, Mark A.^b | Ashford, J. Wesson^c | Casadesus, Gemma^d | Robakis, Nikolaos K.^e | Wolozin, Benjamin^f | Perry, George^{b; g} | Zhu, Xiongwei^b | Greco, Steven J.^a | Sarkar, Sraboni^a

Affiliations: [a] Neurotez, Inc., Bridgewater, New Jersey, USA | [b] Department of Pathology, Case Western Reserve University, Cleveland, OH, USA | [c] Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, CA, USA | [d] Department of Neurosciences, Case Western Reserve University, Cleveland, OH, USA | [e] Departments of Psychiatry and Neuroscience, Center for Neurodegeneration, Mount Sinai School of Medicine, New York University, New York, NY, USA | [f] Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA | [g] College of Sciences, University of Texas at San Antonio, San Antonio, TX, USA

Correspondence: [*] Corresponding author: Nikolaos Tezapsidis, Ph.D., Neurotez, Inc., 991 Highway 22, Suite 200A, Bridgewater, NJ 08807, USA. Tel.: +1 908 998 1340; Fax: +1 908 864 8957; E-mail: ntezapsidis@neurotez.com.

Abstract: Adipocyte-derived leptin appears to regulate a number of features defining Alzheimer's disease (AD) at the molecular and physiological level. Leptin has been shown to reduce the amount of extracellular amyloid beta, both in cell culture and animal models, as well as to reduce tau phosphorylation in neuronal cells. Importantly, chronic administration of leptin resulted in a significant improvement in the cognitive performance of transgenic animal models. In AD, weight loss often precedes the onset of dementia and the level of circulating leptin is inversely proportional to the severity of cognitive decline. It is speculated that a deficiency in leptin levels or function may contribute to systemic and CNS abnormalities leading to disease progression. Furthermore, a leptin deficiency may aggravate insulin-controlled pathways, known to be aberrant in AD. These observations suggest that a leptin replacement therapy may be beneficial for these patients.

Keywords: AICAR, AMP-activated kinase, amyloid-β, glycogen synthase kinase-3, leptin, tau

DOI: 10.3233/JAD-2009-1021

Journal: Journal of Alzheimer's Disease, vol. 16, no. 4, pp. 731-740, 2009