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Amyloid Beta Peptide Is an Endogenous Negative Allosteric Modulator of Leptin Receptor.
Cecon, Erika; Lhomme, Tori; Maurice, Tangui; Luka, Marine; Chen, Min; Silva, Anisia; Wauman, Joris; Zabeau, Lennart; Tavernier, Jan; Prévot, Vincent; Dam, Julie; Jockers, Ralf.
Afiliación
  • Cecon E; Institut Cochin, Université de Paris, CNRS, INSERM, Paris, France.
  • Lhomme T; Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, EGID, DistAlz, Lille Neuroscience & Cognition, UMR-S 1172, Lille, France.
  • Maurice T; MMDN, University of Montpellier, EPHE, INSERM, UMR_S1198, Montpellier, France.
  • Luka M; Institut Cochin, Université de Paris, CNRS, INSERM, Paris, France.
  • Chen M; Institut Cochin, Université de Paris, CNRS, INSERM, Paris, France.
  • Silva A; Institut Cochin, Université de Paris, CNRS, INSERM, Paris, France.
  • Wauman J; VIB Center for Medical Biotechnology, Department of Biomolecular Medicine, University of Ghent, Ghent, Belgium.
  • Zabeau L; VIB Center for Medical Biotechnology, Department of Biomolecular Medicine, University of Ghent, Ghent, Belgium.
  • Tavernier J; VIB Center for Medical Biotechnology, Department of Biomolecular Medicine, University of Ghent, Ghent, Belgium.
  • Prévot V; Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, EGID, DistAlz, Lille Neuroscience & Cognition, UMR-S 1172, Lille, France.
  • Dam J; Institut Cochin, Université de Paris, CNRS, INSERM, Paris, France.
  • Jockers R; Institut Cochin, Université de Paris, CNRS, INSERM, Paris, France, ralf.jockers@inserm.fr.
Neuroendocrinology ; 111(4): 370-387, 2021.
Article en En | MEDLINE | ID: mdl-32335558
INTRODUCTION: Metabolic dysfunction is now recognized as a pivotal component of Alzheimer's disease (AD), the most common dementia worldwide. However, the precise molecular mechanisms linking metabolic dysfunction to AD remain elusive. OBJECTIVE: Here, we investigated the direct impact of soluble oligomeric amyloid beta (Aß) peptides, the main molecular hallmark of AD, on the leptin system, a major component of central energy metabolism regulation. METHODS: We developed a new time-resolved fluorescence resonance energy transfer-based Aß binding assay for the leptin receptor (LepR) and studied the effect of Aß on LepR function in several in vitro assays. The in vivo effect of Aß on LepR function was studied in an Aß-specific AD mouse model and in pro-opiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus. RESULTS: We revealed specific and high-affinity (Ki = 0.1 nM) binding of Aß to LepR. Pharmacological characterization of this interaction showed that Aß binds allosterically to the extracellular domain of LepR and negatively affects receptor function. Negative allosteric modulation of LepR by Aß was detected at the level of signaling pathways (STAT-3, AKT, and ERK) in vitroand in vivo. Importantly, the leptin-induced response of POMC neurons, key players in the regulation of metabolic function, was completely abolished in the presence of Aß. CONCLUSION: Our data indicate that Aß is a negative allosteric modulator of LepR, resulting in impaired leptin action, and qualify LepR as a new and direct target of Aß oligomers. Preventing the interaction of Aß with LepR might improve both the metabolic and cognitive dysfunctions in AD condition.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Núcleo Arqueado del Hipotálamo / Proopiomelanocortina / Péptidos beta-Amiloides / Leptina / Regulación Alostérica / Receptores de Leptina / Enfermedad de Alzheimer Límite: Animals / Humans / Male Idioma: En Revista: Neuroendocrinology Año: 2021 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Suiza
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Núcleo Arqueado del Hipotálamo / Proopiomelanocortina / Péptidos beta-Amiloides / Leptina / Regulación Alostérica / Receptores de Leptina / Enfermedad de Alzheimer Límite: Animals / Humans / Male Idioma: En Revista: Neuroendocrinology Año: 2021 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Suiza