PDF(Pubmed)
Abstract：
BACKGROUND: Despite extensive studies on the neurobiological correlates of traumatic brain injury (TBI), little is known about its molecular determinants on long-term consequences, such as dementia and Alzheimer\'s disease (AD).
METHODS: Here, we carried out behavioural studies and an extensive biomolecular analysis, including inflammatory cytokines, gene expression and the combination of LC-HRMS and MALDI-MS Imaging to elucidate the targeted metabolomics and lipidomics spatiotemporal alterations of brains from wild-type and APP-SWE mice, a genetic model of AD, at the presymptomatic stage, subjected to mild TBI.
RESULTS: We found that brain injury does not affect cognitive performance in APP-SWE mice. However, we detected an increase of key hallmarks of AD, including Aβ1-42 levels and BACE1 expression, in the cortices of traumatized transgenic mice. Moreover, significant changes in the expanded endocannabinoid (eCB) system, or endocannabinoidome (eCBome), occurred, including increased levels of the endocannabinoid 2-AG in APP-SWE mice in both the cortex and hippocampus, and N-acylserotonins, detected for the first time in the brain. The gene expression of enzymes for the biosynthesis and inactivation of eCBs and eCB-like mediators, and some of their main molecular targets, also underwent significant changes. We also identified the formation of heteromers between cannabinoid 1 (CB1) and serotonergic 2A (5HT2A) receptors, whose levels increased in the cortex of APP-SWE mTBI mice, possibly contributing to the exacerbated pathophysiology of AD induced by the trauma.
CONCLUSIONS: Mild TBI induces biochemical changes in AD genetically predisposed mice and the eCBome may play a role in the pathogenetic link between brain injury and neurodegenerative disorders also by interacting with the serotonergic system.
METHODS: Here, we carried out behavioural studies and an extensive biomolecular analysis, including inflammatory cytokines, gene expression and the combination of LC-HRMS and MALDI-MS Imaging to elucidate the targeted metabolomics and lipidomics spatiotemporal alterations of brains from wild-type and APP-SWE mice, a genetic model of AD, at the presymptomatic stage, subjected to mild TBI.
RESULTS: We found that brain injury does not affect cognitive performance in APP-SWE mice. However, we detected an increase of key hallmarks of AD, including Aβ1-42 levels and BACE1 expression, in the cortices of traumatized transgenic mice. Moreover, significant changes in the expanded endocannabinoid (eCB) system, or endocannabinoidome (eCBome), occurred, including increased levels of the endocannabinoid 2-AG in APP-SWE mice in both the cortex and hippocampus, and N-acylserotonins, detected for the first time in the brain. The gene expression of enzymes for the biosynthesis and inactivation of eCBs and eCB-like mediators, and some of their main molecular targets, also underwent significant changes. We also identified the formation of heteromers between cannabinoid 1 (CB1) and serotonergic 2A (5HT2A) receptors, whose levels increased in the cortex of APP-SWE mTBI mice, possibly contributing to the exacerbated pathophysiology of AD induced by the trauma.
CONCLUSIONS: Mild TBI induces biochemical changes in AD genetically predisposed mice and the eCBome may play a role in the pathogenetic link between brain injury and neurodegenerative disorders also by interacting with the serotonergic system.
摘要：
背景：尽管对创伤性脑损伤（TBI）的神经生物学相关性进行了广泛的研究，对其长期后果的分子决定因素知之甚少，如痴呆和阿尔茨海默病（AD）。
方法：这里，我们进行了行为研究和广泛的生物分子分析，包括炎症细胞因子,基因表达以及LC-HRMS和MALDI-MS成像的组合，以阐明野生型和APP-SWE小鼠大脑的靶向代谢组学和脂质组学时空改变，AD的遗传模型，在症状前阶段，受到轻度TBI。
结果：我们发现脑损伤不会影响APP-SWE小鼠的认知能力。然而,我们发现AD的关键标志增加，包括Aβ1-42水平和BACE1表达，在受创伤的转基因小鼠的皮层中。此外，内源性大麻素（eCB）系统的显着变化，或内源性大麻素（eCBome），发生,包括APP-SWE小鼠皮质和海马中内源性大麻素2-AG的水平升高，和N-酰基血清素,第一次在大脑中发现。eCB和eCB样介质生物合成和失活酶的基因表达，以及它们的一些主要分子靶标，也发生了重大变化。我们还确定了大麻素1（CB1）和5-羟色胺能2A（5HT2A）受体之间异聚体的形成，其在APP-SWEmTBI小鼠皮质中的水平增加，可能导致由创伤引起的AD的病理生理学恶化。
结论：轻度TBI在AD遗传易感小鼠中诱导生化改变，eCBome可能通过与5-羟色胺能系统相互作用在脑损伤和神经退行性疾病之间的发病联系中发挥作用。
方法：这里，我们进行了行为研究和广泛的生物分子分析，包括炎症细胞因子,基因表达以及LC-HRMS和MALDI-MS成像的组合，以阐明野生型和APP-SWE小鼠大脑的靶向代谢组学和脂质组学时空改变，AD的遗传模型，在症状前阶段，受到轻度TBI。
结果：我们发现脑损伤不会影响APP-SWE小鼠的认知能力。然而,我们发现AD的关键标志增加，包括Aβ1-42水平和BACE1表达，在受创伤的转基因小鼠的皮层中。此外，内源性大麻素（eCB）系统的显着变化，或内源性大麻素（eCBome），发生,包括APP-SWE小鼠皮质和海马中内源性大麻素2-AG的水平升高，和N-酰基血清素,第一次在大脑中发现。eCB和eCB样介质生物合成和失活酶的基因表达，以及它们的一些主要分子靶标，也发生了重大变化。我们还确定了大麻素1（CB1）和5-羟色胺能2A（5HT2A）受体之间异聚体的形成，其在APP-SWEmTBI小鼠皮质中的水平增加，可能导致由创伤引起的AD的病理生理学恶化。
结论：轻度TBI在AD遗传易感小鼠中诱导生化改变，eCBome可能通过与5-羟色胺能系统相互作用在脑损伤和神经退行性疾病之间的发病联系中发挥作用。
