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饮用水中铅暴露通过阿尔茨海默病基因依赖机制导致成年小鼠认知障碍。

Exposure to Lead in Drinking Water Causes Cognitive Impairment via an Alzheimer's Disease Gene-Dependent Mechanism in Adult Mice.

机构信息

Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.

Department of Plant and Soil Sciences, University of Kentucky Martin-Gatton College of Agriculture, Food, and Environment, Lexington, KY, USA.

出版信息

J Alzheimers Dis. 2024;100(s1):S291-S304. doi: 10.3233/JAD-240640.

Abstract

BACKGROUND

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.

OBJECTIVE

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.

摘要

背景

铅(Pb)暴露是一个主要的公共卫生问题,可能通过污染的土壤、空气、食物或水在日常生活中或从事危险职业时发生。尽管 Pb 长期以来一直被认为是儿童神经发育毒物,但最近越来越多的流行病学研究表明,累积的低水平 Pb 暴露可能导致成年人与年龄相关的神经功能障碍。成年人环境 Pb 暴露与迟发性阿尔茨海默病(AD)和痴呆风险增加有关。

目的

虽然这种联系的生物学机制尚不清楚,但有人提出 Pb 暴露可能通过改变 AD 相关基因的表达,并可能通过激活 AD 相关病理的分子途径来增加 AD 的风险。

方法

我们使用一系列具有 APPΔNL/ΔNL x PS1P264L/P264L 致 AD 基因突变的基因修饰小鼠和 Leprdb/db 小鼠进行 Pb 暴露研究,后者赋予了对血管病理的易感性。

结果

我们的数据表明,尽管成年小鼠中的 Pb 暴露会损害认知功能,但这种影响与淀粉样蛋白病理的增加或常见 AD 相关基因的表达变化无关。Pb 暴露还导致血压显著升高,这是 Pb 的已知作用。有趣的是,尽管血压升高与基因型无关,但只有携带 AD 相关突变的小鼠才会出现认知功能障碍,尽管脑血管病理没有明显变化。

结论

这些结果提出了一种可能性,即成年人中与 Pb 暴露相关的痴呆风险增加可能与其随后与预先存在或正在发展的 AD 相关神经病理学的相互作用有关。

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