Bibliographic
In this study the authors investigated the Aβ-lowering effects of prolonged leptin treatment on the CRND8 transgenic model of AD, to the degree that waspreviously reported for the Tg2576 mouse. In contrast to the Tg2576 studies, treatments here were initiated, and were continued, within the post-plaque period, allowing the evaluation of the effect of treatment on the brain beta amyloid burden. Also, the effect of leptin treatment on cognitive performance was evaluated, using two different experimental paradigms addressing hippocampal functionality. Leptin-treated Tg mice showed significantly reduced levels of Aβ 1-40 in brain extracts (52% reduction, p=0.047) and serum (55% reduction, p=0.049), as detected by ELISA. Data also showed a 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 (APP). This was 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. The biochemical and pathological changes were correlated with behavioral improvements, as early as after 4 weeks of treatment. This was recorded by a novel object recognition test and particularly the contextual and cued fear conditioning test after 8 weeks of treatment.