Research and Development Service, James J. Peters Department of Veterans Affairs Medical Center, Bronx, New York, USA.
Department of Neurology and the Mount Sinai NFL Neurological Care Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
J Neurotrauma. 2021 Nov 15;38(22):3146-3173. doi: 10.1089/neu.2021.0184. Epub 2021 Sep 15.
Public awareness of traumatic brain injury (TBI) in the military increased recently because of the conflicts in Iraq and Afghanistan where blast injury was the most common mechanism of injury. Besides overt injuries, concerns also exist over the potential adverse consequences of subclinical blast exposures, which are common for many service members. A TBI is a risk factor for the later development of neurodegenerative diseases, including Alzheimer disease (AD)-like disorders. Studies of acute TBI in humans and animals have suggested that increased processing of the amyloid precursor protein (APP) toward the amyloid beta protein (Aβ) may explain the epidemiological associations with AD. In a previous study, however, we found in both rat and mouse models of blast overpressure exposure that rather than increasing, rodent brain Aβ42 levels were decreased after acute blast exposure. Here we subjected APP/presenilin 1 transgenic mice (APP/PS1 Tg) to an extended sequence of repetitive low-level blast exposures (34.5 kPa) administered three times per week over eight weeks. If initiated at 20 weeks of age, these repetitive exposures, which were designed to mimic human subclinical blast exposures, reduced anxiety and improved cognition as well as social interactions in APP/PS1 Tg mice, returning many behavioral parameters in APP/PS1 Tg mice to levels of non-transgenic wild type mice. Repetitive low-level blast exposure was less effective at improving behavioral deficits in APP/PS1 Tg mice when begun at 36 weeks of age. While amyloid plaque loads were unchanged, Aβ 42 levels and Aβ oligomers were reduced in the brain of mice exposed to repetitive low-level blast exposures initiated at 20 weeks of age, although levels did not directly correlate with behavioral parameters in individual animals. These results have implications for understanding the nature of blast effects on the brain and their relationship to human neurodegenerative diseases.
公众对军事性创伤性脑损伤（TBI）的认识最近有所提高，这是因为在伊拉克和阿富汗的冲突中，爆炸伤是最常见的损伤机制。除了明显的损伤外，人们还对亚临床爆炸暴露的潜在不良后果表示担忧，而这种情况在许多军人中很常见。TBI 是以后发生神经退行性疾病（包括阿尔茨海默病（AD）样疾病）的危险因素。对人类和动物急性 TBI 的研究表明，淀粉样前体蛋白（APP）向淀粉样β蛋白（Aβ）的加工增加可能解释了与 AD 的流行病学关联。然而，在之前的一项研究中，我们在大鼠和小鼠的爆炸超压暴露模型中发现，急性爆炸暴露后，啮齿动物大脑中的 Aβ42 水平不仅没有增加反而降低了。在这里，我们让 APP/早老素 1 转基因小鼠（APP/PS1 Tg）接受了一系列重复的低水平爆炸暴露（34.5kPa），每周三次，共八周。如果从 20 周龄开始，这些重复的暴露，旨在模拟人类亚临床爆炸暴露，可减轻 APP/PS1 Tg 小鼠的焦虑，改善认知和社交互动，使 APP/PS1 Tg 小鼠的许多行为参数恢复到非转基因野生型小鼠的水平。当从 36 周龄开始重复进行低水平爆炸暴露时，对 APP/PS1 Tg 小鼠的行为缺陷改善效果较差。尽管淀粉样斑块负荷没有变化，但在从 20 周龄开始接受重复低水平爆炸暴露的小鼠的大脑中，Aβ42 水平和 Aβ寡聚物减少了，尽管水平在个体动物中与行为参数没有直接相关。这些结果对理解爆炸对大脑的影响的性质及其与人类神经退行性疾病的关系具有重要意义。
