小柯机器人

近日，德国马克斯普朗克多学科科学研究所Klaus-Armin Nave等研究人员合作发现，髓鞘功能障碍驱动阿尔茨海默病模型中的淀粉样蛋白-β沉积。该项研究成果于2023年5月31日在线发表在《自然》上。

由于少突胶质细胞支持轴突能量代谢和神经元健康，研究人员假设髓鞘完整性的丧失可能是神经元淀粉样β（Aβ）沉积的上游风险因素，这是阿尔茨海默病（AD）的核心神经病理学特征。研究人员确定了髓鞘功能障碍和脱髓鞘损伤的遗传途径是AD小鼠模型中淀粉样蛋白沉积的有力驱动因素。从机制上讲，髓鞘功能障碍导致Aβ生产机制在轴突肿胀中的积累，并增加皮层淀粉样前体蛋白的切割。令人惊讶的是，具有髓鞘功能障碍的AD小鼠缺乏斑块腐蚀的小胶质细胞，尽管其数量总体上有所增加。具有髓鞘缺陷的AD小鼠模型的大量和单细胞转录组学显示，同时诱导出高度相似但不同的疾病相关小胶质细胞特征，分别针对髓鞘损伤和淀粉样斑块。尽管诱导成功，但通常清除淀粉样斑块的淀粉样疾病相关小胶质细胞（DAM）显然对附近的髓鞘损伤无响应。

这些数据提出了一个工作模型，即年龄依赖性的髓鞘结构缺陷直接和间接地促进了Aβ斑块的形成，因此是一个上游的AD风险因素。改善少突胶质细胞的健康和髓鞘的完整性可能是一个有希望的目标，进而推迟AD的发展和减缓其进展。

据了解，AD是痴呆症的主要原因，其发病率随着年龄的增长而迅速增加，但为什么年龄构成了主要的风险因素，人们仍然不甚了解。大脑衰老会影响少突胶质细胞和髓鞘的结构完整性，后者与继发性神经炎症有关。

附：英文原文

Title: Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease

Author: Depp, Constanze, Sun, Ting, Sasmita, Andrew Octavian, Spieth, Lena, Berghoff, Stefan A., Nazarenko, Taisiia, Overhoff, Katharina, Steixner-Kumar, Agnes A., Subramanian, Swati, Arinrad, Sahab, Ruhwedel, Torben, Mbius, Wiebke, Gbbels, Sandra, Saher, Gesine, Werner, Hauke B., Damkou, Alkmini, Zampar, Silvia, Wirths, Oliver, Thalmann, Maik, Simons, Mikael, Saito, Takashi, Saido, Takaomi, Krueger-Burg, Dilja, Kawaguchi, Riki, Willem, Michael, Haass, Christian, Geschwind, Daniel, Ehrenreich, Hannelore, Stassart, Ruth, Nave, Klaus-Armin

Issue&Volume: 2023-05-31

Abstract: The incidence of Alzheimer’s disease (AD), the leading cause of dementia, increases rapidly with age, but why age constitutes the main risk factor is still poorly understood. Brain ageing affects oligodendrocytes and the structural integrity of myelin sheaths1, the latter of which is associated with secondary neuroinflammation2,3. As oligodendrocytes support axonal energy metabolism and neuronal health4,5,6,7, we hypothesized that loss of myelin integrity could be an upstream risk factor for neuronal amyloid-β (Aβ) deposition, the central neuropathological hallmark of AD. Here we identify genetic pathways of myelin dysfunction and demyelinating injuries as potent drivers of amyloid deposition in mouse models of AD. Mechanistically, myelin dysfunction causes the accumulation of the Aβ-producing machinery within axonal swellings and increases the cleavage of cortical amyloid precursor protein. Suprisingly, AD mice with dysfunctional myelin lack plaque-corralling microglia despite an overall increase in their numbers. Bulk and single-cell transcriptomics of AD mouse models with myelin defects show that there is a concomitant induction of highly similar but distinct disease-associated microglia signatures specific to myelin damage and amyloid plaques, respectively. Despite successful induction, amyloid disease-associated microglia (DAM) that usually clear amyloid plaques are apparently distracted to nearby myelin damage. Our data suggest a working model whereby age-dependent structural defects of myelin promote Aβ plaque formation directly and indirectly and are therefore an upstream AD risk factor. Improving oligodendrocyte health and myelin integrity could be a promising target to delay development and slow progression of AD.

DOI: 10.1038/s41586-023-06120-6

Source: https://www.nature.com/articles/s41586-023-06120-6

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