Leptin inhibits glycogen synthase kinase-3β to prevent tau phosphorylation in neuronal cells

Abstract

We have previously demonstrated that Leptin reduces extracellular amyloid β (Aβ) protein both in vitro and in vivo, and intracellular tau phosphorylation in vitro. Further, we have shown that these effects are dependent on activation of AMP-activated protein kinase (AMPK) in vitro. Herein, we investigated downstream effectors of AMPK signaling directly linked to tau phosphorylation. One such target, of relevance to Alzheimer’s disease (AD), may be GSK-3β, which has been shown to be inactivated by Leptin. We therefore dissected the role of GSK-3β in mediating Leptin’s ability to reducing tau phosphorylation in neuronal cells. Our data suggest that Leptin regulates tau phosphorylation through a pathway involving both AMPK and GSK-3β. This was based on the following: Leptin and the cell-permeable AMPK activator, 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR), reduced tau phosphorylation at AD-relevant sites similarly to the GSK-3β inhibitor, lithium chloride (LiCl). Further, this reduction of tau phosphorylation was mimicked by the downregulation of GSK-3β, achieved using siRNA technology and antagonized by the ectopic overexpression of GSK-3β. These studies provide further insight into Leptin’s mechanism of action in ameliorating AD-related pathways.

Insulin Resistance as Common Molecular Denominator Linking Obesity to Alzheimer’s Disease

“…In rodents, leptin plays a role in APP metabolism, by modulating secretase activity, Aβ peptide formation and clearance [52]. Leptin also seems to promote deactivation of GSK3β [53], and reduced plasma levels of leptin have been associated with an increased risk of AD development [54]. In agreement with this result, we found reduced expression of leptin, activated GSK3β and phosphorylated Tau in the brains of HFD fed mice.…”

Tumor Necrosis Factor-Induced Cerebral Insulin Resistance in Alzheimer's Disease Links Numerous Treatment Rationales

“…Because normal insulin sensitivity keeps GSK-3␤ activity low, administering leptin should also decrease its activation and hyperphosphorylation. This, too, has also been reported in neurons (Greco et al, 2009). The ability of leptin to increase insulin sensitivity has yet to be explored as an explanation for the novel observation that intracerebroventricular injection of leptin dramatically, albeit briefly, improves a wide range of pathologic features in a mouse model of type 1 diabetes (Fujikawa et al, 2010).…”

Obesity as a risk factor for Alzheimer’s disease: the role of adipocytokines

“…Data from cell cultures and AD animal models show evidence of the role of this adipocytokine in amyloid precursor protein (APP) metabolism, namely a reduction of amyloid-beta (Aβ) peptide production by blocking β-secretase activity and increasing Apolipoprotein E (ApoE) dependent Aβ uptake (Fewlass et al 2004). Moreover, leptin seems to promote phosphorylation (and deactivation) of glycogen synthase kinase beta (GSK-3β), the main responsible for abnormal tau phosphorylation (Greco et al 2009). Additionally, Li et al (2012) demonstrated that obese leptin-resistant-mice (db/db) had multiple AD-like brain changes including increased phospho-tau and Aβ as well as decreased synaptic proteins, with consequent impairment of their performance in cognitive tasks.…”