Department of Biomedical & Molecular Sciences, Faculty of Health Sciences, Queen's University, Kingston, ON, Canada.
J Alzheimers Dis. 2021;79(4):1547-1561. doi: 10.3233/JAD-201024.
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.
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.
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).
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.
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.
氧化应激导致的神经元损伤在迟发性/年龄相关性阿尔茨海默病（LOAD）的发展中很重要。我们基于醛脱氢酶 2（ALDH2）基因缺失，建立了一种与氧化应激相关的 LOAD 小鼠模型，ALDH2 是一种对于内源性醛类（来自于脂质过氧化）解毒非常重要的酶。与野生型（WT）小鼠相比，敲除（KO）小鼠表现出 AD 样病理和识别及空间记忆的进行性下降。这种进展可能具有由氧化损伤引起的形态学基础。
我们在背侧海马 CA1 区（dCA1）进行形态计量学分析，以确定神经元结构的改变是否有助于解释 3 至 12 月龄 KO 小鼠进行性认知障碍。
通过 Golgi-Cox 染色后分支结构分析和 Sholl 分析，对 WT 小鼠（148 个神经元）与 KO 小鼠（180 个神经元）的树突形态进行定量分析。
WT 和 KO 小鼠在 3 月龄时 dCA1 锥体神经元的形态和复杂性相似。然而，到 6 月龄时，KO 小鼠的顶树突和基底树突长度、树突复杂性和棘密度显著降低，并且这种情况一直持续到 9 和 12 月龄。脂质过氧化产物 4-羟基壬烯醛蛋白加合物的免疫染色显示，dCA1（但不包括腹侧 CA1）的染色在 3 个月时显著增加，并且一直持续到 12 个月。
这种特定的、进行性的 dCA1 氧化损伤增加发生在 KO 小鼠可检测到的突触修剪之前，这与研究表明背侧海马损伤主要损害认知记忆一致。
