In a paper in the Journal of Alzheimer's Disease, we demonstrate that the oxysterol 27-hydroxycholesterol reduces leptin levels and increases levels of both Aβ and phosphorylated tau in organotypic slices from adult rabbit hippocampus. Interestingly, we show that treatment with leptin reversed the 27-OHC-induced increase in Aβ and phosphorylated tau by decreasing the levels of BACE-1 and GSK-3β, respectively. Our results suggest that cholesterol metabolites induce AD-like pathology by altering leptin signaling.

References:
Marwarha G, Dasari B, Prasanthi JR, Schommer J, Ghribi O. Leptin is Involved in Accumulation of Amyloid-beta and Tau Phosphorylation Induced by 27-Hydroxycholesterol in Organotypic Slices from Adult Rabbit Hippocampus. J Alzheimers Dis. 2009 Dec 7. Abstract

View all comments by Othman Ghribi

Comment by Mark A. Smith, Steven Greco, Jane M. Johnston, J. Wesson Ashford, George Perry, Gemma Casadesus, Nikolaos Tezapsidis

Leptin—A Key Pathogenic Modulator in Alzheimer Disease
The finding that high levels of leptin are associated with a reduced incidence of Alzheimer disease (Lieb et al., 2009) is consistent with data from our laboratories showing that: 1) leptin lowers amyloid-β protein in vitro and in vivo (Fewlass et al., 2004); 2) leptin-mediated reductions of amyloid-β in transgenic animals are associated with improved cognition (Greco et al., 2010); and 3) leptin reduces tau phosphorylation (Greco et al., 2008) through AMPK (Greco et al., 2009b) and GSK3β (Greco et al., 2009a). These findings led us (Fewlass et al., 2004; Tezapsidis et al., 2009) and others (Erol, 2008; Lieb et al., 2009) to suggest that leptin offers significant promise as a novel therapeutic strategy for Alzheimer disease (see Business Wire article).

References:
Erol A (2008) An integrated and unifying hypothesis for the metabolic basis of sporadic Alzheimer's disease. J Alzheimers Dis 13(3): 241-53. Abstract

Fewlass DC, Noboa K, Pi-Sunyer FX, Johnston JM, Yan SD, Tezapsidis N (2004) Obesity-related leptin regulates Alzheimer's Abeta. Faseb J 18(15): 1870-8. Abstract

Greco SJ, Bryan KJ, Sarkar S, Zhu X, Smith MA, Ashford JW, Johnston JM, Tezapsidis N, Casadesus G (2010) Chronic leptin supplementation ameliorates pathology and improves cognitive performance in a transgenic mouse model of Alzheimer's disease. J Alzheimers Dis. Abstract

Greco SJ, Sarkar S, Casadesus G, Zhu X, Smith MA, Ashford JW, Johnston JM, Tezapsidis N (2009a) Leptin inhibits glycogen synthase kinase-3beta to prevent tau phosphorylation in neuronal cells. Neurosci Lett 455(3): 191-4. Abstract

Greco SJ, Sarkar S, Johnston JM, Tezapsidis N (2009b) Leptin regulates tau phosphorylation and amyloid through AMPK in neuronal cells. Biochem Biophys Res Commun 380(1): 98-104. Abstract

Greco SJ, Sarkar S, Johnston JM, Zhu X, Su B, Casadesus G, Ashford JW, Smith MA, Tezapsidis N (2008) Leptin reduces Alzheimer's disease-related tau phosphorylation in neuronal cells. Biochem Biophys Res Commun 376(3): 536-41. Abstract

Lieb W, Beiser AS, Vasan RS, Tan ZS, Au R, Harris TB, Roubenoff R, Auerbach S, DeCarli C, Wolf PA, Seshadri S (2009) Association of plasma leptin levels with incident Alzheimer disease and MRI measures of brain aging. Jama 302(23): 2565-72. Abstract

Tezapsidis N, Johnston JM, Smith MA, Ashford JW, Casadesus G, Robakis NK, Wolozin B, Perry G, Zhu X, Greco SJ, Sarkar S (2009) Leptin: a novel therapeutic strategy for Alzheimer's disease. J Alzheimers Dis 16(4): 731-40. Abstract

View all comments by John (Wes) Ashford
View all comments by Gemma Casadesus
View all comments by Steven Greco
View all comments by Jane Johnston
View all comments by George Perry
View all comments by Mark A. Smith
View all comments by Nikolaos Tezapsidis