■铅(Pb)的暴露是一个主要的公共卫生问题,可能通过污染的土壤发生,空气,食物,或者水,无论是在日常生活中,或在危险职业中工作。尽管铅长期以来被认为是儿童的神经发育毒物,最近越来越多的流行病学研究表明,低水平铅暴露可能导致成人年龄相关的神经功能障碍。成年期环境铅暴露与晚发性阿尔茨海默病(AD)和痴呆的风险有关。
■尽管这种联系背后的生物学机制尚不清楚,已经提出铅暴露可能通过改变AD相关基因的表达而增加AD的风险,可能,通过激活AD相关病理的分子途径。
■我们使用一系列转基因小鼠研究了铅暴露,这些小鼠在淀粉样蛋白前体蛋白和早老素1(APPΔNL/ΔNLxPS1P264L/P264L)中引起AD敲入突变,与Leprdb/db小鼠杂交以赋予血管病理学易感性。
■我们的数据表明,尽管成年小鼠的铅暴露会损害认知功能,这种作用与淀粉样蛋白病理学的增加或常见AD相关基因表达的变化无关.铅暴露也导致血压显著升高,众所周知的铅的作用。有趣的是,尽管血压升高与基因型无关,只有携带AD相关突变的小鼠出现认知功能障碍,尽管脑血管病理学没有明显变化。
■这些结果提出了一种可能性,即成人与铅暴露相关的痴呆风险增加可能与其随后与预先存在或发展中的AD相关神经病理学的相互作用有关。
UNASSIGNED: Exposure to lead (Pb) is a major public health problem that could occur through contaminated soil, air, food, or water, either during the course of everyday life, or while working in hazardous occupations. Although Pb has long been known as a neurodevelopmental toxicant in children, a recent and growing body of epidemiological research indicates that cumulative, low-level Pb exposure likely drives age-related neurologic dysfunction in adults. Environmental Pb exposure in adulthood has been linked to risk of late-onset Alzheimer\'s disease (AD) and dementia.
UNASSIGNED: Although the biological mechanism underlying this link is unknown, it has been proposed that Pb exposure may increase the risk of AD via altering the expression of AD-related genes and, possibly, by activating the molecular pathways underlying AD-related pathology.
UNASSIGNED: We investigated Pb exposure using a line of genetically modified mice with AD-causing knock-in mutations in the amyloid precursor protein and presenilin 1 (APPΔNL/ΔNL x PS1P264L/P264L) that had been crossed with Leprdb/db mice to impart vulnerability to vascular pathology.
UNASSIGNED: Our data show that although Pb exposure in adult mice impairs cognitive function, this effect is not related to either an increase in amyloid pathology or to changes in the expression of common AD-related genes. Pb exposure also caused a significant increase in blood pressure, a well known effect of Pb. Interestingly, although the increase in blood pressure was unrelated to genotype, only mice that carried AD-related mutations developed cognitive dysfunction, in spite of showing no significant change in cerebrovascular pathology.
UNASSIGNED: These results raise the possibility that the increased risk of dementia associated with Pb exposure in adults may be tied to its subsequent interaction with either pre-existing or developing AD-related neuropathology.