Department of Physical Therapy and Rehabilitation Science, University of California, San Francisco, CA 94143, USA.
Brain and Spinal Injury Center, University of California, San Francisco, CA 94110, USA.
Int J Mol Sci. 2018 Nov 26;19(12):3753. doi: 10.3390/ijms19123753.
Traumatic brain injury (TBI) is of particular concern for the aging community since there is both increased incidence of TBI and decreased functional recovery in this population. In addition, TBI is the strongest environmental risk factor for development of Alzheimer's disease and other dementia-related neurodegenerative disorders. Critical changes that affect cognition take place over time following the initial insult. Our previous work identified immune system activation as a key contributor to cognitive deficits observed in aged animals. Using a focal contusion model in the current study, we demonstrate a brain lesion and cavitation formation, as well as prolonged blood⁻brain barrier breakdown. These changes were associated with a prolonged inflammatory response, characterized by increased microglial cell number and phagocytic activity 30 days post injury, corresponding to significant memory deficits. We next aimed to identify the injury-induced cellular and molecular changes that lead to chronic cognitive deficits in aged animals, and measured increases in complement initiation components C1q, C3, and CR3, which are known to regulate microglial⁻synapse interactions. Specifically, we found significant accumulation of C1q on synapses within the hippocampus, which was paralleled by synapse loss 30 days post injury. We used genetic and pharmacological approaches to determine the mechanistic role of complement initiation on cognitive loss in aging animals after TBI. Notably, both genetic and pharmacological blockade of the complement pathway prevented memory deficits in aged injured animals. Thus, therapeutically targeting early components of the complement cascade represents a significant avenue for possible clinical intervention following TBI in the aging population.
创伤性脑损伤（TBI）是老龄化社会特别关注的问题，因为在这个人群中，TBI 的发病率增加，功能恢复减少。此外，TBI 是阿尔茨海默病和其他与痴呆相关的神经退行性疾病发展的最强环境风险因素。在初始损伤后，随着时间的推移，会发生影响认知的关键变化。我们之前的工作确定免疫系统激活是导致老年动物认知缺陷的关键因素。在当前的研究中，我们使用局灶性挫伤模型，证明了脑损伤和空洞形成，以及血脑屏障的持续破坏。这些变化与延长的炎症反应有关，其特征是 30 天后小胶质细胞数量和吞噬活性增加，对应明显的记忆缺陷。我们接下来的目的是确定导致老年动物慢性认知缺陷的损伤诱导的细胞和分子变化，并测量补体起始成分 C1q、C3 和 CR3 的增加，这些成分已知可调节小胶质细胞-突触相互作用。具体来说，我们发现 C1q 在海马体突触内的明显积累，这与 30 天后的突触丢失相平行。我们使用遗传和药理学方法来确定补体起始在 TBI 后老年动物认知丧失中的机制作用。值得注意的是，补体途径的遗传和药理学阻断都可以防止老年受伤动物的记忆缺陷。因此，针对补体级联的早期成分进行治疗可能是 TBI 后老龄化人群临床干预的一个重要途径。
