Mechanism of pathological aging of brain by using transgenic mice

我们首先检查了表达人β APP 695 ΔNL的转基因小鼠（Tg）（APPsw小鼠：Hsiao K et al. Science 1996），以阐明沉积在这些小鼠脑中的淀粉样β蛋白（Aβ）的特征。在8个月大的小鼠中，海马和大脑皮层出现了巨大的核心斑块（CP）。12月龄小鼠大脑皮质和蛛网膜下腔的部分小血管出现弥漫性斑块（DP）和淀粉样血管病（AA），并随年龄增加而增多。这些神经病理学结构由具有N-和C-末端修饰的各种Aβ物质组成，如AD脑的那些。CP周围神经突起内存在过度磷酸化的tau蛋白和βAPP。在核心斑块中发现神经元细胞丢失以及突触丢失。8月龄时脑内Aβ40和Aβ42的含量已达高峰，并随Aβ淀粉样变性的进展而显著增加。被动回避实验显示，这些小鼠在8.5月龄时有明显的记忆障碍。接下来，为了阐明载脂蛋白E（ApoE）是否促进体内Aβ沉积，我们检查了共表达APPsw和大鼠Apo E（对应于人ApoE 4）（（βAPP（+）ApoE（+）Tg）的Tg的脑和血浆。βAPP（+）ApoE（+）Tg与β APP（+）ApoE（-）Tg在4月龄和8月龄时的CP、DP和AA程度无差异。12月龄时，βAPP（+）ApoE（+）Tg组的CP、DP和AA程度均大于βAPP（+）ApoE（-）Tg组。βAPP（+）ApoE（+）Tg组脑内Aβ40和Aβ42水平分别比βAPP（+）ApoE（-）Tg组高12%和60%。此外，βAPP（+）ApoE（+）Tg组血浆Aβ40水平也比βAPP（+）ApoE（-）Tg组高40%。因此，这些发现表明ApoE通过增加Aβ浓度加速Aβ沉积。

We first examined transgenic mice (Tg) expressing human βAPP695 ΔNL (APPsw mice : Hsiao K et al. Science 1996) to clarify the character of amyloid β protein (Aβ) deposited in brains of these mice. In 8-month-old mice, giant cored plaques (CP) appeared in the hippocampus and the cerebral cortex. Diffuse plaques (DP) and amyloid angiopathy (AA) in some small vessels of cerebral cortex and subaracnoidal space were recognized in 12-month-old mice, and increased with age. These neuropathological structures consisted of various Aβ species with both N-and C- terminal modifications such as those of AD brains. Accumulation of hyperphosphorylated tau as well as _βAPP were observed in dystrophic neurites surrounding CP. Neuronal cell loss as well as synaptic loss were found in cored plaques. The substantial amounts of Aβ40 and Aβ42 in brains at the age of 8 months were detected, and remarkably increased with the evolution of Aβ amyloidosis. Passive avoidance test revealed that these mice have significant memory impairment at the age of 8.5 months. Thus, APPsw mice are useful models for examining the mechanism of AD pathology.Next, to clarify whether Apolipoprotein E(ApoE) promotes deposition of Aβ in vivo, we examined both brains and plasma of Tg that coexpress APPsw and rat Apo E (corresponding to human ApoE4)((βAPP(+)ApoE(+) Tg). There were no differences in the degree of CP, DP, and AA of between βAPP(+)ApoE(+) Tg and βAPP(+)ApoE(-) Tg at the age of 4 and 8 months. However, at the age of 12 months, degree of CP, DP, and AA in βAPP(+)ApoE(+) Tg was greater than those of βAPP(+)ApoE(-) Tg. The levels of both Aβ40 and Aβ42 in brains of βAPP(+)ApoE(+) Tg were higher than those of βAPP(+)ApoE(-) Tg by 12% and 60%, respectively. Furthermore, the levels of Aβ40 in plasma of βAPP(+)ApoE(+) Tg were also higher than those of βAPP(+)ApoE(-) Tg by 40%. Thus, those findings suggest that ApoE accelerates Aβ deposition by increasing Aβ concentration.