Ujiie Maki, Dickstein Dara L, Carlow Douglas A, Jefferies Wilfred A
Biotechnology Laboratory, University of British Columbia, Vancouver V6T 1Z3, Canada.
Microcirculation. 2003 Dec;10(6):463-70. doi: 10.1038/sj.mn.7800212.
To establish the generality of cerebrovascular pathology frequently observed with Alzheimer disease, we have assessed blood-brain barrier (BBB) integrity using the Alzheimer disease model Tg2576 mice in which cognitive deficits and neuritic plaque formation develop around 10-12 months of age.
We assessed BBB integrity using well-established methods involving albumin and Evans blue uptake and introduce the use of a novel perfusion protocol using succinimidyl ester of carboxyfluorescein diacetate.
BBB permeability is increased in the cerebral cortex of 10-month-old Tg2576 mice preceding Alzheimer disease pathology presentation. Furthermore, when compared with their nontransgenic littermates, 4-month-old Tg2576 mice exhibit compromised BBB integrity in some areas of the cerebral cortex. An age-related increase in albumin uptake by the brains of Tg2576 mice, compared with nontransgenic mice, was also observed. These findings were supported by quantitative Evans blue analysis (p = 0.07, two-way analysis of variance).
A breakdown of BBB was evident in young 4- to 10-month-old Tg2576 mice. Compromised barrier function could explain the mechanisms of Abeta entry into the brain observed in experimental Alzheimer disease vaccination models. Such structural changes to the BBB caused by elevated Abeta could play a central role in Alzheimer disease development and might define an early point of intervention for designing effective therapy against the disease.
为确定阿尔茨海默病中常见的脑血管病理学特征的普遍性，我们使用阿尔茨海默病模型Tg2576小鼠评估了血脑屏障（BBB）的完整性，该模型在10 - 12月龄时会出现认知缺陷和神经炎性斑块形成。
我们使用涉及白蛋白和伊文思蓝摄取的成熟方法评估BBB完整性，并引入了一种使用羧基荧光素二乙酸琥珀酰亚胺酯的新型灌注方案。
在阿尔茨海默病病理学表现出现之前，10月龄Tg2576小鼠的大脑皮质中BBB通透性增加。此外，与非转基因同窝小鼠相比，4月龄Tg2576小鼠在大脑皮质的某些区域表现出BBB完整性受损。与非转基因小鼠相比，还观察到Tg2576小鼠大脑对白蛋白摄取的年龄相关性增加。这些发现得到了伊文思蓝定量分析的支持（p = 0.07，双向方差分析）。
在4至10月龄的年轻Tg2576小鼠中，BBB的破坏很明显。受损的屏障功能可以解释在实验性阿尔茨海默病疫苗接种模型中观察到的β淀粉样蛋白进入大脑的机制。由升高的β淀粉样蛋白引起的BBB的这种结构变化可能在阿尔茨海默病的发展中起核心作用，并可能为设计针对该疾病的有效治疗方法确定一个早期干预点。
