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 (Aβ) 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 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. RESULTS We revealed specific and high-affinity (Ki = 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 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 Aβ. CONCLUSION 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.

中文翻译：

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淀粉样β肽是瘦素受体的内源性负变构调节剂。

引言 代谢功能障碍现在被认为是阿尔茨海默病 (AD) 的关键组成部分，阿尔茨海默病是全世界最常见的痴呆症。然而，将代谢功能障碍与 AD 联系起来的精确分子机制仍然难以捉摸。目的 在这里，我们研究了可溶性寡聚淀粉样蛋白 β (Aβ) 肽（AD 的主要分子标志）对瘦素系统（中枢能量代谢调节的主要组成部分）的直接影响。方法我们开发了一种新的基于时间分辨荧光共振能量转移的瘦素受体 (LepR) 的 Aβ 结合试验，并在几个体外试验中研究了 Aβ 对 LepR 功能的影响。在 Aβ 特异性 AD 小鼠模型和下丘脑弓状核的前阿黑皮素 (POMC) 神经元中研究了 Aβ 对 LepR 功能的体内影响。结果我们揭示了 Aβ 与 LepR 的特异性和高亲和力（Ki = 0.1 nM）结合。这种相互作用的药理学特征表明，Aβ 与 LepR 的细胞外结构域变构结合并对受体功能产生负面影响。在体外和体内的信号通路（STAT-3、AKT 和 ERK）水平上检测到 Aβ 对 LepR 的负变构调节。重要的是，在 Aβ 存在的情况下，瘦素诱导的 POMC 神经元（代谢功能调节的关键参与者）的反应被完全消除。结论 我们的数据表明，Aβ 是 LepR 的负变构调节剂，导致瘦素作用受损，并使 LepR 成为 Aβ 寡聚体的新的直接靶标。阻止 Aβ 与 LepR 的相互作用可能会改善 AD 条件下的代谢和认知功能障碍。