Functional and transcriptional profiling of microglial activation during the chronic phase of TBI identifies an age-related driver of poor outcome in old mice.
Functional and transcriptional profiling of microglial activation during the chronic phase of TBI identifies an age-related driver of poor outcome in old mice.
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DOI：
10.1007/s11357-022-00562-y
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发表时间：
2022-06
期刊：
影响因子：
5.6
通讯作者：
Wu, Junfang
中科院分区：
文献类型：
--
作者：
Ritzel, Rodney M.;Li, Yun;Lei, Zhuofan;Carter, Jordan;He, Junyun;Choi, Harry M. C.;Khan, Niaz;Li, Hui;Allen, Samantha;Lipinski, Marta M.;Faden, Alan, I;Wu, Junfang
老年创伤性脑损伤（TBI）患者的死亡率高于年轻人，预后较差。老年在多大程度上改变了TBI后的长期恢复和慢性小胶质细胞活化尚不清楚，并且严重缺乏老年小鼠治疗效果的证据。本研究旨在确定TBI后期年龄相关结局的潜在炎症机制。控制皮质撞击用于在年轻和老年雄性C57 BL/6小鼠中诱导中度TBI。在损伤后12周，老年小鼠表现出更高的死亡率，更差的功能结果，更大的病变体积和增加的小胶质细胞活化。转录组学分析确定了与慢性损伤大脑中疾病相关的小胶质细胞特征一致的年龄和TBI特异性基因变化，包括与补体、吞噬作用和自噬途径相关的基因变化。小胶质细胞吞噬和自噬功能的失调伴随着老年小鼠神经炎症的增加。作为这些途径具有功能重要性的原理证明，我们在TBI后连续8周在饮用水中施用自噬增强剂海藻糖。与蔗糖对照组相比，用海藻糖治疗的老年小鼠在TBI后后期表现出增强的功能恢复和减少的小胶质细胞活化。我们的数据表明，小胶质细胞在正常衰老和TBI的自噬调节中发生慢性变化，这些变化与较差的功能结局相关。因此，增强自噬可能是TBI的一种有前途的临床治疗策略，特别是在老年患者中。在线版本包含补充材料，可通过10.1007/s11357-022-00562-y获得。
Elderly patients with traumatic brain injury (TBI) have greater mortality and poorer outcomes than younger individuals. The extent to which old age alters long-term recovery and chronic microglial activation after TBI is unknown, and evidence for therapeutic efficacy in aged mice is sorely lacking. The present study sought to identify potential inflammatory mechanisms underlying age-related outcomes late after TBI. Controlled cortical impact was used to induce moderate TBI in young and old male C57BL/6 mice. At 12 weeks post-injury, aged mice exhibited higher mortality, poorer functional outcomes, larger lesion volumes, and increased microglial activation. Transcriptomic analysis identified age- and TBI-specific gene changes consistent with a disease-associated microglial signature in the chronically injured brain, including those involved with complement, phagocytosis, and autophagy pathways. Dysregulation of phagocytic and autophagic function in microglia was accompanied by increased neuroinflammation in old mice. As proof-of-principle that these pathways have functional importance, we administered an autophagic enhancer, trehalose, in drinking water continuously for 8 weeks after TBI. Old mice treated with trehalose showed enhanced functional recovery and reduced microglial activation late after TBI compared to the sucrose control group. Our data indicate that microglia undergo chronic changes in autophagic regulation with both normal aging and TBI that are associated with poorer functional outcome. Enhancing autophagy may therefore be a promising clinical therapeutic strategy for TBI, especially in older patients. The online version contains supplementary material available at 10.1007/s11357-022-00562-y.
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