Analysis of pathogenetic mechanism of Alzheimer's disease using trisomy 16 chimera mice

16三体小鼠(TS16)被认为是人类21三体(唐氏综合征)的动物模型。由于编码淀粉样前体蛋白的基因位于小鼠的16号染色体上，因此本研究的目的是检验TS16是否也可以作为分析阿尔茨海默病(AD)中β淀粉样蛋白沉积机制的有用的实验系统。为此，我们必须使用以下方法挽救TS16中枢神经系统(CNS)的细胞，因为TS16的大部分(如果不是全部)在出生后不能存活。首先，我们建立了一套用聚集法生产TS16 2n嵌合体小鼠的系统。到目前为止获得的嵌合鼠直到出生一年后才表现出任何行为异常。第二，将TS16胎儿中枢神经系统组织移植到正常成年小鼠脑内。详细的组织学分析。是观察β淀粉样蛋白是否真的沉积在这些小鼠大脑中所必需的。第三，建立了胎儿中枢神经系统神经元原代培养体系。我们发现在TS16基底前脑胆碱能神经元胆碱乙酰转移酶活性不能被外源性神经生长因子(NGF)诱导。而且TS16胎儿大脑中的NGF含量增加。这些结果将为研究AD胆碱能功能障碍的机制提供线索。

Trisomy 16 mice (Ts16) have been considered as an animal model for human trisomy 21 (Down syndrome). The object of this study is to examine whether Ts16 can also be a useful experimental system for analyzing the mechanism of beta amyloid protein deposition in Alzheimer's disease (AD), because the gene encoding amyloid precursor protein was found to be located on mouse chromosome 16. For this purpose, we have to rescue cells of the Ts16 central nervous system (CNS) using the following methods, since most, if not all, of the Ts16 cannot survive after birth. First, we have established a system to produce Ts16 2n chimera mice using the aggregation method. The chimeric mice so far obtained do not show any behaviological abnormalities until 1 year after birth. Second, Ts16 fetal CNS tissues have been transplanted into normal adult mouse brains. Detailed histological analyses. are necessary to see whether beta amyloid is actually deposited in the brains of these mice. Third, a primary culture system for fetal CNS neurons has been established. We have found that in Ts16 basal forebrain cholinergic neurons choline acetyltransferase activity cannot be induced by exogenousely added nerve growth factor (NGF). and that NGF content is increased in Ts16 fetal brains. These results will give clues to study the mechanism of cholinergic dysfunction in AD.