Effects of advanced age upon astrocyte-specific responses to acute traumatic brain injury in mice
Effects of advanced age upon astrocyte-specific responses to acute traumatic brain injury in mice
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DOI：
10.1186/s12974-020-01800-w
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发表时间：
2020-04-14
影响因子：
9.3
通讯作者：
Morganti, Josh M.
中科院分区：
文献类型：
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作者：
Early, Alexandria N.;Gorman, Amy A.;Morganti, Josh M.
老年人是创伤性脑损伤（TBI）致残的最高风险人群。星形胶质细胞是脑中数量最多的胶质细胞，是脑功能所必需的，然而关于星形胶质细胞在TBI后老化脑中的独特反应知之甚少。方法我们的方法检测了年轻成年4月龄小鼠与老年18月龄小鼠在TBI后1、3和7天的星形胶质细胞。我们选择这些时间点来跨越从急性损伤到可能不可逆的组织损伤和残疾的过渡的关键时期。使用两种方法通过年龄相互作用来定义星形胶质细胞对TBI的贡献：（1）组织组织学和形态学表型，和（2）来自受损脑的富集星形胶质细胞的转录组学。结果发现衰老对TBI诱导的星形胶质细胞功能丧失有深远的影响，星形胶质细胞功能丧失是维持水转运和水肿所必需的，即水通道蛋白4。老年人的大脑也表现出一个渐进性恶化的星形胶质细胞增生的功能损伤后的时间。此外，clasmatodendrosis，一个认识不足的星形胶质细胞病变，被发现是显着增加，在老年人的大脑，但不是在年轻的大脑。作为TBI的一个功能，我们观察到这些星形胶质细胞数量的短暂折射，其在老年脑损伤后7天反弹。转录组学数据表明，与年轻小鼠相比，TBI后老年小鼠中归因于反应性星形胶质细胞、炎症反应、补体途径和突触支持的基因发生了不成比例的变化。此外，我们的数据强调，TBI并没有引起与先前定义的反应性星形胶质细胞增生的“A1/A2”二分法的明确对齐。结论总的来说，我们的研究结果指向TBI后老年星形胶质细胞的渐进表型，我们假设是适应不良的，对潜在的可改变的星形胶质细胞特异性机制提出了新的见解，这些机制可能是老年大脑对创伤的脆弱性增加的基础。
Background Older-age individuals are at the highest risk for disability from a traumatic brain injury (TBI). Astrocytes are the most numerous glia in the brain, necessary for brain function, yet there is little known about unique responses of astrocytes in the aged-brain following TBI. Methods Our approach examined astrocytes in young adult, 4-month-old, versus aged, 18-month-old mice, at 1, 3, and 7 days post-TBI. We selected these time points to span the critical period in the transition from acute injury to presumably irreversible tissue damage and disability. Two approaches were used to define the astrocyte contribution to TBI by age interaction: (1) tissue histology and morphological phenotyping, and (2) transcriptomics on enriched astrocytes from the injured brain. Results Aging was found to have a profound effect on the TBI-induced loss of astrocyte function needed for maintaining water transport and edema-namely, aquaporin-4. The aged brain also demonstrated a progressive exacerbation of astrogliosis as a function of time after injury. Moreover, clasmatodendrosis, an underrecognized astrogliopathy, was found to be significantly increased in the aged brain, but not in the young brain. As a function of TBI, we observed a transitory refraction in the number of these astrocytes, which rebounded by 7 days post-injury in the aged brain. Transcriptomic data demonstrated disproportionate changes in genes attributed to reactive astrocytes, inflammatory response, complement pathway, and synaptic support in aged mice following TBI compared to young mice. Additionally, our data highlight that TBI did not evoke a clear alignment with the previously defined "A1/A2" dichotomy of reactive astrogliosis. Conclusions Overall, our findings point toward a progressive phenotype of aged astrocytes following TBI that we hypothesize to be maladaptive, shedding new insights into potentially modifiable astrocyte-specific mechanisms that may underlie increased fragility of the aged brain to trauma.