Zawia Nasser H, Basha M Riyaz
Neurotoxicology and Epigenomics Lab, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston 02881, USA.
Rev Neurosci. 2005;16(4):325-37. doi: 10.1515/revneuro.2005.16.4.325.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose clinical manifestations appear in old age. The hallmark pathological features of AD (amyloid plaques and associated proteins) are present in normal aging indivduals, suggesting that AD may result from the acceleration of normal age-related processes in the brain. The sporadic nature of most AD cases strongly argues for an environmental link that may drive AD pathogenesis; however, it is unclear when this environmental stress may occur. Therefore it is important to identify an environmental trigger(s) and to pinpoint the period during which such factors pose the greatest risk. Recently, we reported that developmental exposure of rats to the xenobiotic metal lead (Pb) resulted in a delayed overexpression (20 months later) of the amyloid precursor protein (APP) and its amyloidogenic Abeta product. Similarly, aged monkeys exposed to Pb as infants also responded in the same way. These data suggest that environmental influences occurring during brain development predetermine the expression and regulation of APP later in life, potentially influencing the course of amyloidogenesis, and argue for both an environmental trigger and a developmental origin of AD. In this review, we present evidence for the developmental basis of neurodegeneration and discuss mechanisms that may explain how perturbations during development can have long-term or delayed consequences in the aging brain.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，其临床表现出现在老年阶段。AD的标志性病理特征（淀粉样斑块及相关蛋白）在正常衰老个体中也存在，这表明AD可能是大脑中正常年龄相关进程加速所致。大多数AD病例的散发性有力地表明存在一种可能驱动AD发病机制的环境关联；然而，尚不清楚这种环境压力何时会出现。因此，确定环境触发因素并精确指出这些因素构成最大风险的时期非常重要。最近，我们报告称，大鼠在发育过程中接触外源性金属铅（Pb）会导致淀粉样前体蛋白（APP）及其淀粉样生成产物Aβ延迟过表达（20个月后）。同样，幼年时接触铅的老年猴子也有相同反应。这些数据表明，大脑发育过程中发生的环境影响预先决定了APP在生命后期的表达和调控，可能影响淀粉样蛋白生成过程，并支持AD存在环境触发因素和发育起源。在这篇综述中，我们展示了神经退行性变发育基础的证据，并讨论了可能解释发育过程中的扰动如何在衰老大脑中产生长期或延迟后果的机制。
