Division of Molecular Psychiatry and Alzheimer Ph.D. Graduate School, Department of Psychiatry, University of Goettingen, von-Siebold-Str. 5, 37075 Goettingen, Germany.
Neurobiol Aging. 2010 Jul;31(7):1153-63. doi: 10.1016/j.neurobiolaging.2008.07.022. Epub 2008 Sep 3.
Loss of cholinergic neurons in the Nucleus Basalis of Meynert in Alzheimer's disease (AD) patients was one of the first discoveries of neuron loss in AD. Despite an intense focus on the cholinergic system in AD, the reason for this cholinergic neuron loss is yet unknown. In the present study we examined Abeta-induced pathology and neuron loss in the cholinergic system of the bigenic APP/PS1KI mouse model. Expression of the APP transgene was found in ChAT-positive neurons of motor nuclei accompanied by robust intracellular Abeta accumulation, whereas no APP expressing neurons and thus no intracellular Abeta accumulation were found in neither the forebrain or pons complexes, nor in the caudate putamen. This expression pattern was used as a model system to study the effect of intra- and extracellular Abeta accumulation on neuron loss in the cholinergic system. Stereological quantification revealed a loss of ChAT-positive neurons in APP/PS1KI mice only in the motor nuclei Mo5 and 7N accumulating intracellular Abeta. This study supports the hypothesis of intracellular Abeta accumulation as an early pathological alteration contributing to cell death in AD.
阿尔茨海默病（AD）患者基底前脑胆碱能神经元丧失是 AD 中神经元丧失的最早发现之一。尽管人们对 AD 中的胆碱能系统进行了深入研究，但这种胆碱能神经元丧失的原因仍不清楚。在本研究中，我们检查了双转基因 APP/PS1KI 小鼠模型中胆碱能系统中 Abeta 诱导的病理和神经元丧失。发现 APP 转基因在运动核中的 ChAT 阳性神经元中表达，伴随着强烈的细胞内 Abeta 积累，而在前脑或桥脑复合体中，以及尾状核壳中均未发现表达 APP 的神经元，因此也没有细胞内 Abeta 积累。这种表达模式被用作研究细胞内和细胞外 Abeta 积累对胆碱能系统中神经元丧失影响的模型系统。体视学定量显示，只有在积累细胞内 Abeta 的运动核 Mo5 和 7N 中，APP/PS1KI 小鼠中的 ChAT 阳性神经元才会丧失。这项研究支持了细胞内 Abeta 积累作为导致 AD 中细胞死亡的早期病理改变的假说。
