背景:创伤性脑损伤(TBI)是阿尔茨海默病(AD)的重要危险因素,越来越多的证据支持适应性免疫B和T细胞在TBI和AD发病机制中的作用。我们先前鉴定了TBI后B细胞和主要组织相容性复合物II类(MHCII)相关的不变链肽(CLIP)阳性B细胞扩增。我们还表明,TBI后拮抗CLIP与MHCII抗原呈递沟的结合会急剧减少CLIP脾B细胞,并具有神经保护作用。本研究调查了在5xFAD阿尔茨海默病小鼠模型中拮抗CLIP的慢性效应,有和没有TBI。
方法:12周龄雄性野生型(WT)和5xFAD小鼠给予CLIP拮抗剂肽(CAP)或赋形剂,在假手术或外侧液体撞击损伤(FPI)后30分钟一次。分析包括流式细胞术分析硬膜膜和脾脏中的免疫细胞,大脑的组织病理学分析,磁共振扩散张量成像,脑血管分析,以及随后6个月的运动和神经行为功能评估。
结果:与年龄匹配的WT小鼠相比,9个月大的5xFAD小鼠在脑膜中具有明显更多的CLIPB细胞。用CAP的一次性处理显著减少了5xFAD小鼠中的该群体。重要的是,CAP还提高了一些免疫力,组织病理学,在随后的六个月中,5xFAD小鼠的神经行为障碍。尽管FPI没有进一步升高脑膜CLIP+B细胞,它确实否定了CAP减少5xFAD小鼠脑膜CLIPB细胞的能力。3月龄FPI在5xFAD小鼠中加剧了AD病理的某些方面,包括进一步减少海马神经发生,增加CA3中的斑块沉积,改变小胶质细胞增生,破坏脑血管结构.损伤后的CAP治疗改善了一些但不是全部的FPI效应。
BACKGROUND: Traumatic brain injury (TBI) is a significant risk factor for Alzheimer\'s disease (AD), and accumulating evidence supports a role for adaptive immune B and T cells in both TBI and AD pathogenesis. We previously identified B cell and major histocompatibility complex class II (MHCII)-associated invariant chain peptide (CLIP)-positive B cell expansion after TBI. We also showed that antagonizing CLIP binding to the antigen presenting groove of MHCII after TBI acutely reduced CLIP + splenic B cells and was neuroprotective. The current study investigated the chronic effects of antagonizing CLIP in the 5xFAD Alzheimer\'s mouse model, with and without TBI.
METHODS: 12-week-old male wild type (WT) and 5xFAD mice were administered either CLIP antagonist peptide (CAP) or vehicle, once at 30 min after either sham or a lateral fluid percussion injury (FPI). Analyses included flow cytometric analysis of immune cells in dural meninges and spleen, histopathological analysis of the brain, magnetic resonance diffusion tensor imaging, cerebrovascular analysis, and assessment of motor and neurobehavioral function over the ensuing 6 months.
RESULTS: 9-month-old 5xFAD mice had significantly more CLIP + B cells in the meninges compared to age-matched WT mice. A one-time treatment with CAP significantly reduced this population in 5xFAD mice. Importantly, CAP also improved some of the immune, histopathological, and neurobehavioral impairments in 5xFAD mice over the ensuing six months. Although FPI did not further elevate meningeal CLIP + B cells, it did negate the ability of CAP to reduce meningeal CLIP + B cells in the 5xFAD mice. FPI at 3 months of age exacerbated some aspects of AD pathology in 5xFAD mice, including further reducing hippocampal neurogenesis, increasing plaque deposition in CA3, altering microgliosis, and disrupting the cerebrovascular structure. CAP treatment after injury ameliorated some but not all of these FPI effects.