BACKGROUND Vascular contributions to cognitive impairment and dementia (VCID) are the second leading cause of dementia behind only Alzheimer's disease (AD); however, VCID is commonly found as a co-morbidity with sporadic AD. We have previously established a mouse model of VCID by inducing hyperhomocysteinemia in both wild-type and amyloid depositing mice. While we have shown the time course of neuropathological events in the wild-type mice with hyperhomocysteinemia, the effect of amyloid deposition on this time course remains unknown; therefore, in this study, we determined the time course of neuropathological changes in our mouse model of hyperhomocysteinemia-induced VCID in amyloid depositing mice. METHODS APP/PS1 mice were placed on either a diet deficient in folate and vitamins B6 and B12 and enriched in methionine to induce hyperhomocysteinemia or a control diet for 2, 6, 10, 14, or 18 weeks. Immunohistochemistry and gene expression analysis were used to determine neuroinflammatory changes. Microhemorrhages and amyloid deposition were analyzed using histology and, finally, behavior was assessed using the 2-day radial arm water maze. RESULTS Neuroinflammation, specifically a pro-inflammatory phenotype, was the first pathological change to occur. Specifically, we see a significant increase in gene expression of tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, and interleukin 12a by 6 weeks. This was followed by cognitive deficits starting at 10 weeks. Finally, there is a significant increase in the number of microhemorrhages at 14 weeks on diet as well as redistribution of amyloid from the parenchyma to the vasculature. CONCLUSIONS The time course of these pathologies points to neuroinflammation as the initial, key player in homocysteine-induced VCID co-morbid with amyloid deposition and provides a possible therapeutic target and time points.

中文翻译：

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高同型半胱氨酸淀粉样蛋白沉积小鼠的神经病理学事件的时间进程揭示了淀粉样蛋白变化和脑血管事件之前的早期神经炎症变化。


背景血管导致认知障碍和痴呆（VCID）是导致痴呆的第二大原因，仅次于阿尔茨海默病（AD）。然而，VCID 通常与散发性 AD 并存。我们之前通过在野生型和淀粉样蛋白沉积小鼠中诱导高同型半胱氨酸血症建立了 VCID 小鼠模型。虽然我们已经显示了患有高同型半胱氨酸血症的野生型小鼠中神经病理事件的时间进程，但淀粉样蛋白沉积对此时间进程的影响仍然未知。因此，在这项研究中，我们在淀粉样蛋白沉积小鼠的高同型半胱氨酸血症诱导的 VCID 小鼠模型中确定了神经病理学变化的时间过程。方法 APP/PS1 小鼠被置于缺乏叶酸和维生素 B6 和 B12 并富含蛋氨酸的饮食中以诱导高同型半胱氨酸血症或对照组饮食 2、6、10、14 或 18 周。使用免疫组织化学和基因表达分析来确定神经炎症变化。使用组织学分析微出血和淀粉样蛋白沉积，最后使用 2 天径向臂水迷宫评估行为。结果神经炎症，特别是促炎症表型，是首先发生的病理变化。具体来说，我们发现肿瘤坏死因子 α、白细胞介素 1 β、白细胞介素 6 和白细胞介素 12a 的基因表达在 6 周时显着增加。随后从第 10 周开始出现认知缺陷。最后，饮食第 14 周时微出血的数量显着增加，并且淀粉样蛋白从实质到脉管系统的重新分布。 结论 这些病理的时间过程表明神经炎症是同型半胱氨酸诱导的 VCID 与淀粉样蛋白沉积共病的最初关键因素，并提供了可能的治疗目标和时间点。