Amyloid Beta Peptide Is an Endogenous Negative Allosteric Modulator of Leptin Receptor

<b><i>Introduction:</i></b> 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. <b><i>Objective:</i></b> Here, we investigated the direct impact of soluble oligomeric amyloid beta (Aβ) peptides, the main molecular hallmark of AD, on the leptin system, a major component of central energy metabolism regulation. <b><i>Methods:</i></b> We developed a new time-resolved fluorescence resonance energy transfer-based Aβ binding assay for the leptin receptor (LepR) and studied the effect of Aβ on LepR function in several in vitro assays. The in vivo effect of Aβ on LepR function was studied in an Aβ-specific AD mouse model and in pro-opiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus. <b><i>Results:</i></b> We revealed specific and high-affinity (K_i = 0.1 nM) binding of Aβ to LepR. Pharmacological characterization of this interaction showed that Aβ binds allosterically to the extracellular domain of LepR and negatively affects receptor function. Negative allosteric modulation of LepR by Aβ was detected at the level of signaling pathways (STAT-3, AKT, and ERK) in vitro<i></i>and 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 Aβ. <b><i>Conclusion:</i></b> Our data indicate that Aβ is a negative allosteric modulator of LepR, resulting in impaired leptin action, and qualify LepR as a new and direct target of Aβ oligomers. Preventing the interaction of Aβ with LepR might improve both the metabolic and cognitive dysfunctions in AD condition.