The utilization of the adipocyte hormone, leptin, in models of AD highlight a unique strategy in addressing the potential underlying causes of the sporadic-onset form of the disease [4
]. Abnormal lipid levels within the brain have been associated with Aβ production and clearance. Increased production of Aβ has been shown to induce hyperphosphorylation of tau, thereby promoting NFT formation [17
]. Leptin, which physiologically functions to modulate lipid homeostasis, has been reported to reduce β-secretase activity and Aβ levels in vitro
], and brain Aβ load in vivo
]. Additionally, lower levels of circulating leptin have been observed in AD patients versus healthy controls [6
]. In support, a large prospective study involving 2,871 elderly followed over a period of 4 years showed that low leptin levels were associated with a greater cognitive decline [5
In this study we investigated whether leptin could have a direct effect on the level of tau phosphorylation at sites known to be hyperphosphorylated in AD. Initially using RA-induced, human SY5Y cells, known to express high levels of phosphorylated tau [10
] we confirmed previous studies showing that insulin reduces the level of phosphorylated tau [7
] and in agreement with in vivo
]. Insulin was able to reduce phospho-tau (Ser396
) by 50% at a concentration of 13.8 µM. Strikingly, leptin was 300-fold more potent in this system, being able to achieve the same reduction at a concentration of 46.9 nM (). Insulin is considered a potential therapeutic for AD, thus these findings suggest that leptin may represent an attractive alternative with increased potency.
While the signaling pathways through which insulin mediates its specific effects on tau phosphorylation have been studied extensively [8
], similar pathways activated by leptin to modulate tau have not been reported. To explore leptin’s post-receptor signaling pathways involved in tau phosphorylation, we focused on the energy homeostasis enzyme AMPK (), known to be modulated by leptin [18
]. This enzyme is also known to interact with GSK-3β [20
], which can potentially phosphorylate all phosphoepitopes studied herein. Activation of AMPK with AICAR produced significant changes in tau phosphorylation within 10 min (). In tissues such as skeletal muscle and liver, leptin stimulates fatty acid oxidation via activation of AMPK [19
]. However, within the hypothalamus, leptin has been reported to regulate food intake via inactivation of AMPK [18
]. In this study leptin was capable of activating AMPK in SY5Y cells differentiated by retinoic acid. It remains to be determined whether AMPK in hippocampal neurons responds similarly. These findings suggest that CNS neuronal AMPK may provide a novel therapeutic target for reducing AD-related tau phosphorylation.
Current research is elucidating the mechanism of action of leptin to reduce tau phosphorylation. We demonstrated here that activation of AMPK mimics the leptin effect (). This may be linked to the Akt/GSK-3β pathway that modulates tau phosphorylation; however there are many other kinases and phosphatases that regulate tau at various phosphorylation sites [21
To clearly show the therapeutic value of leptin in treating or preventing NFT formation, in vivo
experiments are necessary. One approach could involve studies with the triple transgenic mouse model of AD, which develop both plaque and tangle pathology [22
]. Validation of our current findings, in vivo
, would demonstrate leptin’s value in selectively targeting both pathologies of AD.
Leptin has been used in clinical trials extensively and has demonstrated an excellent safety profile, even after prolonged treatments. Taken together, our preclinical data demonstrating that leptin ameliorates both Aβ and tau-related pathologies, along with its pharmacological profile, support its use as a novel therapeutic for Alzheimer’s disease.