Background:Neuronal damage resulting from increased oxidative stress is important in the development of late onset/age-related Alzheimer’s disease (LOAD). We have developed an oxidative stress–related mouse model of LOAD based on gene deletion of aldehyde dehydrogenase 2 (ALDH2), an enzyme important for the detoxification of endogenous aldehydes arising from lipid peroxidation. Compared to wildtype (WT) mice, the knockout (KO) mice exhibit AD-like pathologies and a progressive decline in recognition and spatial memory. This progression presumably has a morphological basis induced by oxidative damage. Objective:We performed morphometric analyses in the dorsal hippocampal CA1 region (dCA1) to determine if altered neuronal structure can help account for the progressive cognitive impairment in 3- to 12-month-old KO mice. Methods:Dendritic morphology was quantitatively analyzed by branched structured analysis and Sholl analysis following Golgi-Cox staining in WT mice (148 neurons) versus KO mice (180 neurons). Results:The morphology and complexity of dCA1 pyramidal neurons were similar at age 3 months in WTs and KOs. However, by 6 months there were significant reductions in apical and basal dendritic length, dendrite complexity, and spine density in KO versus WT mice that were maintained through ages 9 and 12 months. Immunostaining for protein adducts of the lipid peroxidation product 4-hydroxynonenal revealed significant increases in staining in dCA1 (but not ventral CA1) by 3 months, increasing through 12 months. Conclusion:This specific and progressive increase in dCA1 oxidative damage preceded detectable synaptic trimming in KO mice, in keeping with studies showing that lesions to dorsal hippocampus primarily impair cognitive memory.

中文翻译：

---

晚发性阿尔茨海默病小鼠模型海马背侧 CA1 区域与年龄相关的神经元退化

背景：氧化应激增加导致的神经元损伤在晚发型/与年龄相关的阿尔茨海默病 (LOAD) 的发展中很重要。我们开发了一种基于醛脱氢酶 2 (ALDH2) 基因缺失的氧化应激相关小鼠模型，该酶对脂质过氧化引起的内源性醛的解毒很重要。与野生型 (WT) 小鼠相比，敲除 (KO) 小鼠表现出类似 AD 的病理学和认知和空间记忆的逐渐下降。这种进展可能具有氧化损伤诱导的形态学基础。目的：我们对海马背侧 CA1 区 (dCA1) 进行了形态计量分析，以确定改变的神经元结构是否有助于解释 3 至 12 个月大的 KO 小鼠的进行性认知障碍。方法：在 WT 小鼠（148 个神经元）与 KO 小鼠（180 个神经元）的 Golgi-Cox 染色后，通过分支结构分析和 Sholl 分析对树突形态进行定量分析。结果：WTs和KOs在3个月大时dCA1锥体神经元的形态和复杂性相似。然而，到 6 个月时，KO 与 WT 小鼠的顶端和基底树突长度、树突复杂性和脊柱密度显着降低，这些小鼠一直维持到 9 个月和 12 个月。脂质过氧化产物 4-羟基壬烯醛的蛋白质加合物的免疫染色显示 dCA1（但不是腹侧 CA1）的染色在 3 个月内显着增加，持续 12 个月。结论：这种 dCA1 氧化损伤的特异性和渐进性增加先于可检测到的 KO 小鼠突触修剪，