Stark Neurosciences Research Institute, Indiana University, School of Medicine, Indianapolis, IN 46202, USA.
Department of Medical and Molecular Genetics, Indiana University, School of Medicine, Indianapolis, IN 46202, USA.
Acta Neuropathol Commun. 2024 Sep 19;12(1):154. doi: 10.1186/s40478-024-01855-3.
Aging is the greatest known risk factor for most neurodegenerative diseases. Myelin degeneration is an early pathological indicator of these diseases and a normal part of aging; albeit, to a lesser extent. Despite this, little is known about the contribution of age-related myelin degeneration on neurodegenerative disease. Microglia participate in modulating white matter events from demyelination to remyelination, including regulation of (de)myelination by the microglial innate immune receptor triggering receptor expressed on myeloid cells 2 (TREM2). Here, we demonstrate Trem2-deficiency aggravates and accelerates age-related myelin degeneration in the striatum. We show TREM2 is necessary for remyelination by recruiting reparative glia and mediating signaling that promotes OPC differentiation/maturation. In response to demyelination, TREM2 is required for phagocytosis of large volumes of myelin debris. In addition to lysosomal regulation, we show TREM2 can modify the ER stress response, even prior to overt myelin debris, that prevents lipid accumulation and microglial dysfunction. These data support a role for Trem2-dependent interactions in age-related myelin degeneration and suggest a basis for how early dysfunctional microglia could contribute to disease pathology through insufficent repair, defective phagocytosis, and the ER stress response.
衰老是大多数神经退行性疾病的最大已知风险因素。髓鞘变性是这些疾病的早期病理指标，也是衰老的正常部分；尽管程度较轻。尽管如此，人们对与年龄相关的髓鞘变性对神经退行性疾病的贡献知之甚少。小胶质细胞参与调节从脱髓鞘到髓鞘再生的白质事件，包括小胶质细胞先天免疫受体触发表达在髓样细胞 2（TREM2）调节（去）髓鞘。在这里，我们证明 Trem2 缺乏加剧和加速纹状体与年龄相关的髓鞘变性。我们表明，TREM2 通过招募修复性胶质细胞并介导促进少突胶质细胞前体细胞分化/成熟的信号来促进髓鞘再生是必需的。在脱髓鞘反应中，TREM2 需要吞噬大量的髓鞘碎片。除了溶酶体调节外，我们还表明，TREM2 可以修饰内质网应激反应，甚至在明显的髓鞘碎片之前，从而防止脂质积累和小胶质细胞功能障碍。这些数据支持 Trem2 依赖性相互作用在与年龄相关的髓鞘变性中的作用，并表明早期功能失调的小胶质细胞如何通过不足的修复、缺陷的吞噬作用和内质网应激反应导致疾病病理学的基础。
