Leptin Reduces Pathology and Improves Memory in a Transgenic Mouse Model of Alzheimer's Disease

Article type: Research Article

Authors: Greco, Steven J.^{a; 1} | Bryan, Kathryn J.^{b; 1} | Sarkar, Sraboni^a | Zhu, Xiongwei^c | Smith, Mark A.^c | Ashford, J. Wesson^d | Johnston, Jane M.^a | Tezapsidis, Nikolaos^{a; *} | Casadesus, Gemma^{b; *}

Affiliations: [a] Neurotez, Inc., Bridgewater, NJ, USA | [b] Department of Neurosciences, Case Western Reserve University, Cleveland, OH, USA | [c] Department of Pathology, Case Western Reserve University, Cleveland, OH, USA | [d] Stanford/VA Aging Clinical Research Center, VA Palo Alto Health Care System, Palo Alto, CA, USA

Correspondence: [*] Correspondence to: 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: [email protected] or Gemma Casadesus, Ph.D., Department of Neurosciences, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106 USA. Tel.: +1 216 368 8503; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Note: [] Handling Editor: Jesus Avila

Abstract: We have previously reported anti-amyloidogenic effects of leptin using in vitro and in vivo models and, more recently, demonstrated the ability of leptin to reduce tau phosphorylation in neuronal cells. The present study examined the efficacy of leptin in ameliorating the Alzheimer's disease (AD)-like pathology in 6-month old CRND8 transgenic mice (TgCRND8) following 8 weeks of treatment. Leptin-treated transgenic mice showed significantly reduced levels of amyloid-β (Aβ)1–40 in both brain extracts (52% reduction, p = 0.047) and serum (55% reduction, p = 0.049), as detected by ELISA, and significant reduction in amyloid burden (47% reduction, p = 0.041) in the hippocampus, as detected by immunocytochemistry. The decrease in the levels of Aβ in the brain correlated with a decrease in the levels of C99 C-terminal fragments of the amyloid-β protein precursor, consistent with a role for β -secretase in mediating the effect of leptin. In addition, leptin-treated TgCRND8 mice had significantly lower levels of phosphorylated tau, as detected by AT8 and anti-tau-Ser396 antibodies. Importantly, after 4 or 8 weeks of treatment, there was no significant increase in the levels of C-reactive protein, tumor necrosis factor-α, and cortisol in the plasma of leptin-treated TgCRND8 animals compared to saline-treated controls, indicating no inflammatory reaction. These biochemical and pathological changes were correlated with behavioral improvements, as early as after 4 weeks of treatment, as recorded by a novel object recognition test and particularly the contextual and cued fear conditioning test after 8 weeks of treatment. Leptin-treated TgCRND8 animals significantly outperformed saline-treated littermates in these behavioral tests. These findings solidly demonstrate the potential for leptin as a disease modifying therapeutic in transgenic animals of AD, driving optimism for its safety and efficacy in humans.

Keywords: Alzheimer's disease, amyloid-β, CRND8, leptin, tau

DOI: 10.3233/JAD-2010-1308

Journal: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1155-1167, 2010