Amyloid Beta Peptide Is An Endogenous Negative Allosteric Modulator Of Leptin Receptor

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 (A beta) 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 A beta binding assay for the leptin receptor (LepR) and studied the effect of A beta on LepR function in several in vitro assays. The in vivo effect of A beta on LepR function was studied in an A beta-specific AD mouse model and in pro-opiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus. Results: We revealed specific and high-affinity (K-i = 0.1 nM) binding of A beta to LepR. Pharmacological characterization of this interaction showed that A beta binds allosterically to the extracellular domain of LepR and negatively affects receptor function. Negative allosteric modulation of LepR by A beta 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 A beta. Conclusion: Our data indicate that A beta is a negative allosteric modulator of LepR, resulting in impaired leptin action, and qualify LepR as a new and direct target of A beta oligomers. Preventing the interaction of A beta with LepR might improve both the metabolic and cognitive dysfunctions in AD condition.