比利时VIB脑与疾病研究中心Joris de Wit，Bart De Strooper和Sara Calafate共同合作，近期取得重要工作进展。他们研究发现MCH系统的早期改变将阿尔茨海默病小鼠模型中的异常神经元活动和睡眠障碍联系起来。相关研究成果2023年5月15日在线发表于《自然—神经科学》杂志上。

据介绍，早期阿尔茨海默病（AD）与海马过度活跃和睡眠质量下降有关。

研究人员发现，稳态机制暂时性抵消了App^NL-G-F小鼠对CA1神经元兴奋性驱动的增加，但这种机制在老年小鼠中失败了。空间转录组学分析确定Pmch是App^NL-G-F小鼠适应性反应的一部分。Pmch编码黑色素浓缩激素（MCH），该激素在睡眠活跃的下丘脑外侧神经元中产生，该神经元投射到CA1并调节记忆。研究人员发现，在App^NL-G-F小鼠中，MCH下调突触传递，调节海马神经元的放电速率稳态，并逆转对CA1神经元增加的兴奋性驱动。App^NL-G-F小鼠在快速眼动（REM）睡眠中花费的时间较少。App^NL-G-F小鼠和AD患者在CA1投射MCH轴突的形态上表现出渐进性变化。

总之，这一研究结果表明，MCH系统在早期AD中是脆弱的，并表明MCH系统功能受损会导致异常兴奋性驱动和睡眠缺陷，从而损害海马依赖性功能。

附：英文原文

Title: Early alterations in the MCH system link aberrant neuronal activity and sleep disturbances in a mouse model of Alzheimer’s disease

Author: Calafate, Sara, zturan, Gkhan, Thrupp, Nicola, Vanderlinden, Jeroen, Santa-Marinha, Lusa, Morais-Ribeiro, Rafaela, Ruggiero, Antonella, Bozic, Ivan, Rusterholz, Thomas, Lorente-Echeverra, Blanca, Dias, Marcelo, Chen, Wei-Ting, Fiers, Mark, Lu, Ashley, Vlaeminck, Ine, Creemers, Eline, Craessaerts, Katleen, Vandenbempt, Joris, van Boekholdt, Luuk, Poovathingal, Suresh, Davie, Kristofer, Thal, Dietmar Rudolf, Wierda, Keimpe, Oliveira, Tiago Gil, Slutsky, Inna, Adamantidis, Antoine, De Strooper, Bart, de Wit, Joris

Issue&Volume: 2023-05-15

Abstract: Early Alzheimer’s disease (AD) is associated with hippocampal hyperactivity and decreased sleep quality. Here we show that homeostatic mechanisms transiently counteract the increased excitatory drive to CA1 neurons in AppNL-G-F mice, but that this mechanism fails in older mice. Spatial transcriptomics analysis identifies Pmch as part of the adaptive response in AppNL-G-F mice. Pmch encodes melanin-concentrating hormone (MCH), which is produced in sleep–active lateral hypothalamic neurons that project to CA1 and modulate memory. We show that MCH downregulates synaptic transmission, modulates firing rate homeostasis in hippocampal neurons and reverses the increased excitatory drive to CA1 neurons in AppNL-G-F mice. AppNL-G-F mice spend less time in rapid eye movement (REM) sleep. AppNL-G-F mice and individuals with AD show progressive changes in morphology of CA1-projecting MCH axons. Our findings identify the MCH system as vulnerable in early AD and suggest that impaired MCH-system function contributes to aberrant excitatory drive and sleep defects, which can compromise hippocampus-dependent functions.

DOI: 10.1038/s41593-023-01325-4

Source: https://www.nature.com/articles/s41593-023-01325-4