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

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-Ser 396 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.

Leptin regulation of hippocampal synaptic function in health and disease

“…A recent prospective study found that the incidence of AD was much lower in nonobese individuals with high circulating leptin levels [66], which further supports a link between leptin levels and the incidence of this disease. Studies in rodent AD models have also detected correlations between leptin and neurodegeneration as leptin levels are significantly reduced in APPSwe and CRND8 murine models of AD [67,68].…”

“…Another key pathological hallmark of AD is neurofibrillary tangles comprising hyperphosphorylated tau. Recent studies indicate that leptin regulates the levels of phosphorylated tau, as leptin not only reduces neuronal accumulation of tau but also limits tau phosphorylation via inhibition of GSK3b [68]. In cortical neurons, leptin markedly reduces Ab-stimulated increases in phosphorylated tau (p-tau; [69]).…”

Recognition memory in tree shrew (Tupaia belangeri) after repeated familiarization sessions

“…By contrast, rodents do not provide a good model for assessing detrimental effects on LTM. Nevertheless, to date, almost all NOR tests have been done in rodents and this test is increasingly used in rodent animal models of various diseases including Alzheimer's Disease (Donkin et al, 2010;Greco et al, 2010;Hillen et al, 2010;Lu et al, 2009;Mouri et al, 2007;Nishida et al, 2006;Taglialatela et al, 2009), schizophrenia (Hauser et al, 2009;McLean et al, 2009;Neill et al, 2010;Ozawa et al, 2006;Powell et al, 2007;Vigano et al, 2009), and Down's syndrome (Lockrow et al, 2010). The absence of any external reinforcement in the NOR test is particularly important as it makes it more comparable to memory tests in human, which are normally conducted without the use of positive or negative reinforcers such as food and electric shock (Ennaceur and Delacour, 1988).…”

Leptin Regulation of Synaptic Function at Hippocampal TA-CA1 and SC-CA1 Synapses: Implications for Health and Disease

“…Although most rodent models of AD do not fully replicate the pathological and behavioural characteristics of human AD, attenuated circulating leptin levels have also been detected in various AD models [84,85]. Moreover, a transgenic AD mouse model (APP/PS1) with elevated toxic amyloid-β (Aβ) plaques and memory loss, displays a reduction in Ob-R levels as well as key components of Ob-R signalling, including STAT3 and SOCS3 [86].…”