Cyclic Ozone Exposure Induces Gender-Dependent Neuropathology and Memory Decline in an Animal Model of Alzheimer's Disease
Cyclic Ozone Exposure Induces Gender-Dependent Neuropathology and Memory Decline in an Animal Model of Alzheimer's Disease
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DOI：
10.1093/toxsci/kfv124
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发表时间：
2015-09-01
影响因子：
3.8
通讯作者：
Liu, Rui-Ming
中科院分区：
文献类型：
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作者：
Akhter, Hasina;Ballinger, Carol;Liu, Rui-Ming
阿尔茨海默病（Alzheimer's disease，AD）是老年痴呆症的主要病因之一。虽然早发性（家族性）AD归因于基因突变，但占AD病例95%的迟发性（散发性）AD的原因尚不清楚。在这项研究中，我们表明，暴露6周龄的淀粉样β前体蛋白（APP）/早老素（PS1）过表达小鼠，一个良好的动物模型的AD，和非转基因同窝出生的婴儿到一个循环的O-3暴露协议，模仿环境暴露事件，加速学习/记忆功能丧失的雄性APP/PS1小鼠，但不是在雌性APP/PS1小鼠或非转基因同窝出生的婴儿。与雄性APP/PS1小鼠相比，雌性APP/PS1小鼠的脑淀粉样β肽（A β 42）和A β 40水平较高;然而，O-3暴露对雄性或雌性小鼠的脑A β负荷没有显著影响。我们的研究结果进一步表明，雄性APP/PS1小鼠有较低水平的抗氧化剂（谷胱甘肽和抗坏血酸）和经验丰富的诱导NADPH氧化酶，脂质过氧化反应，神经元凋亡后O-3曝光，与雌性APP/PS1小鼠相比。在非转基因同窝仔中，O-3对任何这些参数均无显著影响。体外研究进一步表明，4-羟基壬烯醛（一种脂质过氧化产物，在O-3暴露的雄性APP/PS1小鼠的血浆和皮质/海马中增加）诱导神经母细胞瘤细胞凋亡。总之，结果表明，O-3暴露本身可能不会导致AD，但可以与遗传风险因素协同作用，加速遗传易感人群中AD的病理生理学。结果还表明，男性可能是更敏感的O-3诱导的神经病理生理比女性由于较低水平的抗氧化剂。
Alzheimer's disease (AD) is a major cause of dementia in the elderly. Although early-onset (familial) AD is attributed to gene mutations, the cause for late-onset (sporadic) AD, which accounts for 95% of AD cases, is unknown. In this study, we show that exposure of 6-week-old amyloid beta precursor protein (APP)/presenilin (PS1) overexpressing mice, a well-established animal model of AD, and nontransgenic littermates to a cyclic O-3 exposure protocol, which mimics environmental exposure episodes, accelerated learning/memory function loss in male APP/PS1 mice but not in female APP/PS1 mice or nontransgenic littermates. Female APP/PS1 mice had higher brain levels of amyloid beta peptide (A beta 42) and A beta 40, compared with male APP/PS1 mice; O-3 exposure, however, had no significant effect on brain A beta load in either male or female mice. Our results further show that male APP/PS1 mice had lower levels of antioxidants (glutathione and ascorbate) and experienced augmented induction of NADPH oxidases, lipid peroxidation, and neuronal apoptosis upon O-3 exposure, compared with female APP/PS1 mice. No significant effect of O-3 on any of these parameters was detected in nontransgenic littermates. In vitro studies further show that 4-hydroxynonenal, a lipid peroxidation product which was increased in the plasma and cortex/hippocampus of O-3-exposed male APP/PS1 mice, induced neuroblastoma cell apoptosis. Together, the results suggest that O-3 exposure per se may not cause AD but can synergize with genetic risk factors to accelerate the pathophysiology of AD in genetically predisposed populations. The results also suggest that males may be more sensitive to O-3-induced neuropathophysiology than females due to lower levels of antioxidants.