title: Dysregulation of leptin signaling in Alzheimer disease: evidence for neuronal leptin resistance.
abstract: Leptin signaling has received considerable attention in the Alzheimer disease (AD) field. Within the past decade, the peptide hormone has been demonstrated to attenuate tau hyperphosphorylation in neuronal cells and to be modulated by amyloid-β. Moreover, a role in neuroprotection and neurogenesis within the hippocampus has been shown in animal models. To further characterize the association between leptin signaling and vulnerable regions in AD, we assessed the profile of leptin and the leptin receptor in AD and control patients. We analyzed leptin levels in CSF, and the concentration and localization of leptin and leptin receptor in the hippocampus. Significant elevations in leptin levels in both CSF and hippocampal tissue of AD patients, compared with age-matched control cases, indicate a physiological up-regulation of leptin in AD. However, the level of leptin receptor mRNA decreased in AD brain and the leptin receptor protein was localized to neurofibrillary tangles, suggesting a severe discontinuity in the leptin signaling pathway. Collectively, our results suggest that leptin resistance in the hippocampus may play a role in the characteristic changes associated with the disease. These findings are the first to demonstrate such dysregulated leptin-signaling circuitry and provide novel insights into the possible role of aberrant leptin signaling in AD. In this study, increased leptin was found in CSF and hippocampus in Alzheimer disease indicating its physiological up-regulation, yet leptin receptor mRNA was decreased and leptin receptor protein was localized to neurofibrillary tangles, suggesting a discontinuity in the leptin signaling pathway. The lack of leptin signaling within degenerating neurons may represent a novel neuronal leptin resistance in Alzheimer disease.
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Bonda
authors.forename: Jeremy G
authors.initials: JG
authors.lastname: Stone
authors.forename: Sandy L
authors.initials: SL
authors.lastname: Torres
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Siedlak
authors.forename: George
authors.initials: G
authors.lastname: Perry
authors.forename: Richard
authors.initials: R
authors.lastname: Kryscio
authors.forename: Gregory
authors.initials: G
authors.lastname: Jicha
authors.forename: Gemma
authors.initials: G
authors.lastname: Casadesus
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
authors.forename: Xiongwei
authors.initials: X
authors.lastname: Zhu
authors.forename: Hyoung-Gon
authors.initials: HG
authors.lastname: Lee
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020738:Leptin / Q000134:cerebrospinal fluid / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000502:physiology; D054411:Receptors, Leptin / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D055815:Young Adult
chemical_list: C515448:LEPR protein, human; D020738:Leptin; D054411:Receptors, Leptin
keywords: Alzheimer disease; leptin; leptin receptor; neurofibrillary tangles; tau
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