Does traumatic brain injury hold the key to the Alzheimer's disease puzzle?
Does traumatic brain injury hold the key to the Alzheimer's disease puzzle?
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DOI：
10.1016/j.jalz.2017.11.007
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发表时间：
2018-04
期刊：
影响因子：
--
通讯作者：
Greig NH
中科院分区：
文献类型：
--
作者：
Becker RE;Kapogiannis D;Greig NH
神经退行性疾病已经成为药物发现和开发的数百个善意努力的墓地。脑震荡和其他创伤性脑损伤（TBI）和阿尔茨海默病（AD）共享许多重叠的病理和可能的临床联系。我们使用Medline和Google Scholar检索了自1995年以来的文献，检索了术语脑震荡、AD和共享神经病理学。我们还研究了TBI动物模型作为转基因（tg）小鼠AD模型的补充，用于通过预防神经元损失来评估AD药物疗效。为了评估TBI/ AD病理学和神经元自身诱导的细胞死亡（凋亡），我们正在研究血浆中的脑细胞外囊泡（EV）和（−）-苯丝氨酸药理学，以在AD和人类动物模型中探索脑震荡和AD的凋亡和共同途径。TBI后神经细胞死亡和多种显著的病理级联反应。许多发展中的病理存在于早期AD中。使用脑震荡动物模型作为tg小鼠的补充提供了AD候选药物预防AD中细胞凋亡和导致痴呆进展的潜力的指示。这种对tg小鼠模型、实验药物（-）-苯丝氨酸和富集神经元来源的血浆衍生EV的体重下降补充，以遵循神经退行性过程的生物标志物，每种和组合显示出作为用于探测AD疾病进展、TBI/AD病理、细胞凋亡和药物对临床前和人类细胞凋亡率的影响的工具的前景。（-）-苯丝氨酸既能对抗许多亚急性TBI后病理，这些病理可能引发临床AD，又在脑震荡和其他动物模型中显示出与在TBI/AD病理存在下直接抑制神经元预编程细胞死亡一致的证据。这些发现可能为扩大TBI体重下降模型的AD临床前tg小鼠研究提供支持，深入了解病理靶点的进展，它们与细胞凋亡的关系，以及针对这些靶点和细胞凋亡的干预时机。这些研究可以证明药物有效和安全地抑制预编程细胞死亡的潜力，作为一种用于击败AD的新药开发策略。
Neurodegenerative disorders have been a graveyard for hundreds of well-intentioned efforts at drug discovery and development. Concussion and other traumatic brain injury (TBI) and Alzheimer’s disease (AD) share many overlapping pathologies and possible clinical links. We searched the literature since 1995 using Medline and Google Scholar for the terms concussion, AD, and shared neuropathologies. We also studied a TBI animal model as a supplement to transgenic (tg) mouse AD models for evaluating AD drug efficacy by preventing neuronal losses. To evaluate TBI/ AD pathologies and neuronal self-induced cell death (apoptosis) we are studying brain Extracellular Vesicles (EVs) in plasma and (−)-phenserine pharmacology to probe, in animal models of AD and humans, apoptosis and pathways common to concussion and AD. Neuronal cell death and a diverse and significant pathological cascade follow TBI. Many of the developing pathologies are present in early AD. The use of an animal model of concussion as a supplement to tg mice provides an indication of an AD drug candidate’s potential for preventing apoptosis and resulting progression towards dementia in AD. This weight drop supplementation to tg mouse models, the experimental drug (−)-phenserine, and plasma derived EVs enriched for neuronal origin to follow biomarkers of neurodegenerative processes, each and in combination show promise as tools useful for probing the progression of disease in AD, TBI/AD pathologies, apoptosis, and drug effects on rates of apoptosis both preclinically and in humans. (−)-Phenserine both countered many subacute post-TBI pathologies that could initiate clinical AD and, in the concussion and other animal models, showed evidence consistent with direct inhibition of neuronal preprogrammed cell death in the presence of TBI/AD pathologies. These findings may provide support for expanding preclinical tg mouse studies in AD with a TBI weight drop model, insights into the progression of pathological targets, their relations to apoptosis, and timing of interventions against these targets and apoptosis. Such studies may demonstrate the potential for drugs to effectively and safely inhibit preprogrammed cell death as a new drug development strategy for use in the fight to defeat AD.
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影响因子：
3.2
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