Leptin regulates tau phosphorylation and amyloid through AMPK in neuronal cells

Abstract

Leptin, which serves as a lipid-modulating hormone to control metabolic energy availability, is decreased in Alzheimer's disease (AD) patients, and serum levels are inversely correlated to severity of dementia. We have previously described the effects of leptin in reducing amyloid β protein both in vitro and in vivo, and tau phosphorylation in vitro. Herein, we systematically investigated the signaling pathways activated by leptin, leading to these molecular endpoints, to better understand its mechanism of action. Inhibition of amyloid β production and tau phosphorylation in leptin-treated human and/or rat neuronal cultures were both dependent on activation of AMP-activated protein kinase (AMPK). Direct stimulation of AMPK with the cell-permeable activator, 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR), replicated leptin's effects and conversely, Compound C, an inhibitor of AMPK, blocked leptin's action. The data implicate that AMPK is a key regulator of both AD-related pathways.

Adenosine monophosphate-activated protein kinase activation mediates the leptin-induced attenuation of cognitive impairment in a streptozotocin-induced rat model

“…Numerous studies have highlighted the important role of AMPK in the pathogenesis of Alzheimer's disease, which is characterized by cognitive impairment (22,23). An in vitro study by Greco et al (24) showed that leptin increased cellular metabolism by activating AMPK to reduce Aβ expression in neurons. A different study also performed by this group (25) demonstrated that leptin directly regulated Aβ through the AMPK pathway.…”

AMPK in the central nervous system: physiological roles and pathological implications

“…67 In addition, leptin-induced AMPK activation is associated with a reduction in Tau phosphorylation. 75 Despite these findings, other evidence sustains an opposite role for AMPK in AD. Interestingly, the activation of AMPK by metformin is protective in females but increases memory dysfunction in males, suggesting a sex-divergent cognitive effect in a murine model of AD.…”

Adipobiology of the brain: From brain diabetes to adipose Alzheimer‘s disease

“…However, the brain (mostly hypothalamus) is not the only target for leptin and other adipokines, as well as the food intake is not the only biological e ect of these adipokines. Rather, some adipokines support various metabolic and cognitive functions and exert both metabo-and neurotrophic actions (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). Current data of adipose-derived neuroendocrine and neurotrophic factors are summarized in Tables 1, 2.…”