Huuha Aleksi M, Norevik Cecilie Skarstad, Coombes Jeff S, Røsbjørgen Ragnhild N, Miguel-Dos-Santos Rodrigo, Moreira José Bianco N, Kobro-Flatmoen Asgeir, Scrimgeour Nathan, Tari Atefe R
Department of Circulation and Medical Imaging, Cardiac Exercise Research Group (CERG), Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
Department of Neurology and Clinical Neurophysiology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
Brain Plast. 2024 May 14;9(1-2):21-41. doi: 10.3233/BPL-230154. eCollection 2024.
Microglia and inflammation play a significant role in Alzheimer's disease (AD). Physical exercise and peripheral signals can influence microglial activity in the brain. Modulating the inflammatory response in the brain may provide therapeutic approaches for AD.
To assess the effects of intravenously administered blood plasma from exercise-trained donor rats on cognitive function, microglia, and cytokine levels in an AD rat model at two different pathological stages; an early pre-plaque stage and a later stage closer to the emergence of extracellular plaques.
Male transgenic McGill-R-Thy1-APP rats aged 2 and 5 months received 14 injections over 6 weeks: 1) plasma from exercise-trained rats (ExPlas), 2) plasma from sedentary rats (SedPlas), or 3) saline. Cognitive function was evaluated in a novel object recognition task. Microglia count and morphology were analyzed in cornu ammonis, dentate gyrus, entorhinal cortex, and subiculum. Amyloid plaque number and size were assessed in the rats with the later treatment start. A multiplex assay was used to measure 23 cytokines in cornu ammonis.
In rats treated from 2 months of age, ExPlas and SedPlas increased number and length of microglial branches in cornu ammonis and dentate gyrus compared to saline. Only ExPlas-treated rats exhibited similar changes in subiculum, while entorhinal cortex showed no differences across treatments. Microglia count remained unaffected. In rats treated from 5 months of age, there were no significant differences in microglia count or morphology or the number or size of amyloid plaques in any brain region. Compared to both other treatments in early pre-plaque stage rats, SedPlas increased TNF-α levels. ExPlas upregulated GM-CSF, IL-18, and VEGF, while SedPlas increased IL-10 compared to saline. In later-stage rats, ExPlas upregulated IL-17, and SedPlas upregulated TNF-α compared to saline. There were no effects of treatments on recognition memory.
Intravenous injections of blood plasma from exercise-trained and sedentary donors differentially modulated microglial morphology and cytokine levels in the AD rat model at an early pre-plaque stage of pathology. Exercised plasma may reduce proinflammatory TNF-α signaling and promote microglial responses to early Aβ accumulation but the lack of treatment effects in the later-stage rats emphasizes the potential importance of treatment timing.
小胶质细胞和炎症在阿尔茨海默病（AD）中起重要作用。体育锻炼和外周信号可影响大脑中的小胶质细胞活性。调节大脑中的炎症反应可能为AD提供治疗方法。
评估静脉注射运动训练供体大鼠的血浆对处于两个不同病理阶段的AD大鼠模型的认知功能、小胶质细胞和细胞因子水平的影响；一个是早期斑块前阶段，另一个是更接近细胞外斑块出现的后期阶段。
2个月龄和5个月龄的雄性转基因麦吉尔-R-Thy1-APP大鼠在6周内接受14次注射：1）运动训练大鼠的血浆（ExPlas），2）久坐大鼠的血浆（SedPlas），或3）生理盐水。在新颖物体识别任务中评估认知功能。分析海马、齿状回、内嗅皮质和下托中的小胶质细胞数量和形态。对后期开始治疗的大鼠评估淀粉样斑块的数量和大小。采用多重检测法测量海马中的23种细胞因子。
在2个月龄开始治疗的大鼠中，与生理盐水相比，ExPlas和SedPlas增加了海马和齿状回中小胶质细胞分支的数量和长度。只有接受ExPlas治疗的大鼠在下托中表现出类似变化，而内嗅皮质在各治疗组之间无差异。小胶质细胞数量未受影响。在5个月龄开始治疗的大鼠中，任何脑区的小胶质细胞数量或形态、淀粉样斑块的数量或大小均无显著差异。与早期斑块前阶段大鼠的其他两种治疗相比，SedPlas增加了TNF-α水平。与生理盐水相比，ExPlas上调了GM-CSF、IL-18和VEGF，而SedPlas增加了IL-10。在后期大鼠中，与生理盐水相比，ExPlas上调了IL-17，SedPlas上调了TNF-α。治疗对识别记忆无影响。
在病理早期斑块前阶段，静脉注射运动训练和久坐供体的血浆对AD大鼠模型中的小胶质细胞形态和细胞因子水平有不同的调节作用。运动后的血浆可能会减少促炎TNF-α信号传导，并促进小胶质细胞对早期Aβ积累的反应，但后期大鼠缺乏治疗效果强调了治疗时机的潜在重要性。
