Institut Cochin, Université de Paris, CNRS, INSERM, Paris, France.
Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, EGID, DistAlz, Lille Neuroscience & Cognition, UMR-S 1172, Lille, France.
Neuroendocrinology. 2021;111(4):370-387. doi: 10.1159/000508105. Epub 2020 Apr 24.
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.
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.
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.
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.
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.
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，AD 是全球最常见的痴呆症。然而，将代谢功能障碍与 AD 联系起来的确切分子机制仍不清楚。
在这里，我们研究了可溶性寡聚淀粉样β（Aβ）肽（AD 的主要分子标志）对瘦素系统的直接影响，瘦素系统是中枢能量代谢调节的主要组成部分。
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）结合测定法，并在几种体外测定中研究了 Aβ 对 LepR 功能的影响。在 AD 特异性小鼠模型和下丘脑弓状核的 pro-opiomelanocortin（POMC）神经元中研究了 Aβ 对 LepR 功能的体内影响。
我们揭示了 Aβ 与 LepR 的特异性和高亲和力（Ki = 0.1 nM）结合。这种相互作用的药物特征表明，Aβ 变构结合 LepR 的细胞外结构域，并负性影响受体功能。在体外和体内均检测到 Aβ 对 LepR 的负变构调节可影响信号通路（STAT-3、AKT 和 ERK）。重要的是，在存在 Aβ 的情况下，瘦素诱导的 POMC 神经元反应（调节代谢功能的关键因素）完全被阻断。
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 寡聚物的新的和直接靶点。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。
