Particulate air pollutants, APOE alleles and their contributions to cognitive impairment in older women and to amyloidogenesis in experimental models.
Particulate air pollutants, APOE alleles and their contributions to cognitive impairment in older women and to amyloidogenesis in experimental models.
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DOI：
10.1038/tp.2016.280
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发表时间：
2017-01-31
影响因子：
6.8
通讯作者：
Chen JC
中科院分区：
文献类型：
--
作者：
Cacciottolo M;Wang X;Driscoll I;Woodward N;Saffari A;Reyes J;Serre ML;Vizuete W;Sioutas C;Morgan TE;Gatz M;Chui HC;Shumaker SA;Resnick SM;Espeland MA;Finch CE;Chen JC
暴露于环境空气中的颗粒物（PM）及其与APOE等位基因的相互作用可能有助于加速脑老化和阿尔茨海默病（AD）的发病机制。来自妇女健康倡议记忆研究（WHIMS）的美国老年妇女队列和实验小鼠模型检查了颗粒空气污染物的神经退行性影响。居住在细颗粒物超过EPA标准的地方，全球认知能力下降和全因痴呆的风险分别增加了81%和92%，APOE 4/4携带者的不良影响更大。雌性EFAD转基因小鼠（5xFAD+/−/人APOE / 3或APOE / 4+/+）暴露于城市纳米PM (nPM) 225小时超过15周后，通过硫黄素S（纤维淀粉样蛋白）和免疫细胞化学（Aβ沉积物）显示脑β-淀粉样蛋白增加，两者都因APOE / 4而加剧。此外，nPM暴露增加了Aβ低聚物，导致海马CA1神经突选择性萎缩，谷氨酸GluR1亚基降低。野生型C57BL/6雌性小鼠也出现npm诱导的CA1萎缩和GluR1降低。神经母细胞瘤细胞（N2a-APP/swe）的体外nPM暴露增加了淀粉样前体蛋白（APP）的前淀粉样变性加工。我们认为，空气中PM暴露会促进老年女性的病理性脑老化，对携带者的影响可能更大。潜在的机制可能涉及大脑Aβ产生增加和海马CA1神经元和谷氨酸受体亚基的选择性改变。
Exposure to particulate matter (PM) in the ambient air and its interactions with APOE alleles may contribute to the acceleration of brain aging and the pathogenesis of Alzheimer's disease (AD). Neurodegenerative effects of particulate air pollutants were examined in a US-wide cohort of older women from the Women's Health Initiative Memory Study (WHIMS) and in experimental mouse models. Residing in places with fine PM exceeding EPA standards increased the risks for global cognitive decline and all-cause dementia respectively by 81 and 92%, with stronger adverse effects in APOE ɛ4/4 carriers. Female EFAD transgenic mice (5xFAD+/−/human APOE ɛ3 or ɛ4+/+) with 225 h exposure to urban nanosized PM (nPM) over 15 weeks showed increased cerebral β-amyloid by thioflavin S for fibrillary amyloid and by immunocytochemistry for Aβ deposits, both exacerbated by APOE ɛ4. Moreover, nPM exposure increased Aβ oligomers, caused selective atrophy of hippocampal CA1 neurites, and decreased the glutamate GluR1 subunit. Wildtype C57BL/6 female mice also showed nPM-induced CA1 atrophy and GluR1 decrease. In vitro nPM exposure of neuroblastoma cells (N2a-APP/swe) increased the pro-amyloidogenic processing of the amyloid precursor protein (APP). We suggest that airborne PM exposure promotes pathological brain aging in older women, with potentially a greater impact in ɛ4 carriers. The underlying mechanisms may involve increased cerebral Aβ production and selective changes in hippocampal CA1 neurons and glutamate receptor subunits.