Macrophage Depletion Ameliorates Peripheral Neuropathy in Aging Mice
Macrophage Depletion Ameliorates Peripheral Neuropathy in Aging Mice
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DOI：
10.1523/jneurosci.3030-17.2018
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发表时间：
2018-05
期刊：
影响因子：
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通讯作者：
Xidi Yuan;D. Klein;S. Kerscher;B. West;J. Weis;I. Katona;R. Martini
中科院分区：
文献类型：
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作者：
Xidi Yuan;D. Klein;S. Kerscher;B. West;J. Weis;I. Katona;R. Martini
衰老被认为是影响神经系统结构和功能的主要危险因素。目前迫切需要克服这种与年龄相关的神经变性的有害影响。在这里，我们发现24月龄的C57BL/6小鼠的周围神经表现出与衰老的人类个体相似的病理改变，而12月龄的成年小鼠则没有这种改变。神经纤维表现为脱髓鞘、再髓鞘和轴突病变。此外，在衰老小鼠中，神经肌肉连接表现出垂死神经病的典型特征，如突触前标记物的下降，与α-班加罗毒素阳性的突触后标记物相关。与这些观察结果一致的是肌肉力量的减少。这些改变伴随着神经内膜巨噬细胞数量的增加，部分包括吞噬性巨噬细胞的特征。在老年人的周围神经活检中可以发现类似的巨噬细胞。为了确定巨噬细胞对衰老小鼠的病理影响，我们通过口服CSF-1R特异性激酶（c-FMS）抑制剂选择性靶向细胞。持续6个月的治疗开始于18个月时退行性变化发生之前，小鼠的巨噬细胞数量减少了约70%，无副作用。引人注目的是，神经结构得到了改善，肌肉力量得到了保留。我们首次表明，年龄相关的周围神经退行性变化是由巨噬细胞驱动的。这些发现可能为通过靶向巨噬细胞治疗老化的周围神经系统变性铺平道路，从而减少虚弱，改善活动能力，并最终提高老年人的生活质量。意义声明衰老是神经系统结构和功能的主要危险因素。在这里，我们发现24个月大的衰老小鼠的周围神经表现出与衰老个体神经相似的退行性改变。在小鼠和人类中，这些改变都伴随着神经内膜巨噬细胞。为了确定巨噬细胞对衰老小鼠的病理影响，我们通过阻断巨噬细胞生存所必需的细胞因子受体，选择性地靶向细胞。治疗可显著减少巨噬细胞数量，显著改善神经结构和肌肉力量。我们首次表明，年龄相关的周围神经退行性变化是由巨噬细胞驱动的。这些发现可能有助于治疗老年人的虚弱和活动能力下降。
Aging is known as a major risk factor for the structure and function of the nervous system. There is urgent need to overcome such deleterious effects of age-related neurodegeneration. Here we show that peripheral nerves of 24-month-old aging C57BL/6 mice of either sex show similar pathological alterations as nerves from aging human individuals, whereas 12-month-old adult mice lack such alterations. Specifically, nerve fibers showed demyelination, remyelination and axonal lesion. Moreover, in the aging mice, neuromuscular junctions showed features typical for dying-back neuropathies, as revealed by a decline of presynaptic markers, associated with α-bungarotoxin-positive postsynapses. In line with these observations were reduced muscle strengths. These alterations were accompanied by elevated numbers of endoneurial macrophages, partially comprising the features of phagocytosing macrophages. Comparable profiles of macrophages could be identified in peripheral nerve biopsies of aging persons. To determine the pathological impact of macrophages in aging mice, we selectively targeted the cells by applying an orally administered CSF-1R specific kinase (c-FMS) inhibitor. The 6-month-lasting treatment started before development of degenerative changes at 18 months and reduced macrophage numbers in mice by ∼70%, without side effects. Strikingly, nerve structure was ameliorated and muscle strength preserved. We show, for the first time, that age-related degenerative changes in peripheral nerves are driven by macrophages. These findings may pave the way for treating degeneration in the aging peripheral nervous system by targeting macrophages, leading to reduced weakness, improved mobility, and eventually increased quality of life in the elderly. SIGNIFICANCE STATEMENT Aging is a major risk factor for the structure and function of the nervous system. Here we show that peripheral nerves of 24-month-old aging mice show similar degenerative alterations as nerves from aging human individuals. Both in mice and humans, these alterations were accompanied by endoneurial macrophages. To determine the pathological impact of macrophages in aging mice, we selectively targeted the cells by blocking a cytokine receptor, essential for macrophage survival. The treatment strongly reduced macrophage numbers and substantially improved nerve structure and muscle strength. We show, for the first time, that age-related degenerative changes in peripheral nerves are driven by macrophages. These findings may be helpful for treatment weakness and reduced mobility in the elderly.