title: Leptin boosts cellular metabolism by activating AMPK and the sirtuins to reduce tau phosphorylation and β-amyloid in neurons.
abstract: Leptin is a pleiotropic hormone primarily secreted by adipocytes. A high density of functional Leptin receptors has been reported to be expressed in the hippocampus and other cortical regions of the brain, the physiological significance of which has not been explored extensively. Alzheimer's disease (AD) is marked by impaired brain metabolism with decreased glucose utilization in those regions which often precede pathological changes. Recent epidemiological studies suggest that plasma Leptin is protective against AD. Specifically, elderly with plasma Leptin levels in the lowest quartile were found to be four times more likely to develop AD than those in the highest quartile. We have previously reported that Leptin modulates AD pathological pathways in vitro through a mechanism involving the energy sensor, AMP-activated protein kinase (AMPK). To this end, we investigated the extent to which activation of AMPK as well as another class of sensors linking energy availability to cellular metabolism, the sirtuins (SIRT), mediate Leptin's biological activity. Leptin directly activated neuronal AMPK and SIRT in cell lines. Additionally, the ability of Leptin to reduce tau phosphorylation and β-amyloid production was sensitive to the AMPK and sirtuin inhibitors, compound C and nicotinamide, respectively. These findings implicate that Leptin normally acts as a signal for energy homeostasis in neurons. Perhaps Leptin deficiency in AD contributes to a neuronal imbalance in handling energy requirements, leading to higher Aβ and phospho-tau, which can be restored by replenishing low Leptin levels. This may also be a legitimate strategy for therapy.
authors.affiliation: Neurotez Inc., Bridgewater, NJ 08807, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Greco
authors.forename: Ashkan
authors.initials: A
authors.lastname: Hamzelou
authors.forename: Jane M
authors.initials: JM
authors.lastname: Johnston
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
authors.forename: J Wesson
authors.initials: JW
authors.lastname: Ashford
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Tezapsidis
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000544:Alzheimer Disease / Q000378:metabolism*; D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D006801:Humans; D020738:Leptin / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000096:biosynthesis*; D037761:Sirtuins / Q000096:biosynthesis*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D020738:Leptin; D016875:tau Proteins; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D037761:Sirtuins