German Dwight C, Nelson Omar, Liang Fen, Liang Chang-Lin, Games Dora
Department of Psychiatry, University of Texas Southwestern Medical School, Dallas, 75390-9070, USA.
J Comp Neurol. 2005 Nov 28;492(4):469-76. doi: 10.1002/cne.20744.
Alzheimer's disease is characterized by neuronal degeneration in the cerebral cortex and hippocampus and subcortical neuronal degeneration in such nuclei as the locus coeruleus (LC). Transgenic mice overexpressing mutant human amyloid precursor protein V717F, PDAPP mice, develop several Alzheimer's disease-like lesions. The present study sought to determine whether there is also loss of LC noradrenergic neurons or evidence of degenerative changes in these animals. PDAPP hemizygous and wild-type littermate control mice were examined at 23 months of age, at a time when there are numerous amyloid-beta (Abeta) plaques in the neocortex and hippocampus. Tissue sections were stained immunohistochemically with an antibody against tyrosine hydroxylase (TH) to identify LC neurons. Computer imaging procedures were used to count the TH-immunoreactive somata in sections through the rostral-caudal extent of the nucleus. There was no loss of LC neurons in the hemizygous mice. In a second experiment, homozygous PDAPP and wild-type mice were examined, at 2 months and 24 months of age. Again there was no age-related loss of neurons in the homozygous animals. In the portion of the LC where neurons reside that project to the cortex and hippocampus, however, the neurons were decreased in size selectively in the 24-month-old transgenic animals. These data indicate that overt LC cell loss does not occur following abundant overexpression of Abeta peptide. However, the selective size reduction of the LC neuronal population projecting to cortical and hippocampal regions containing Abeta-related neuropathology implies that these cells may be subjected to a retrograde-mediated stress.
阿尔茨海默病的特征是大脑皮质和海马体中的神经元退化以及蓝斑（LC）等皮质下核团中的神经元退化。过表达突变型人类淀粉样前体蛋白V717F的转基因小鼠，即PDAPP小鼠，会出现几种类似阿尔茨海默病的病变。本研究旨在确定这些动物中是否也存在蓝斑去甲肾上腺素能神经元的丧失或退化性变化的证据。在23月龄时检查PDAPP半合子和野生型同窝对照小鼠，此时新皮质和海马体中有大量淀粉样β（Aβ）斑块。用抗酪氨酸羟化酶（TH）抗体对组织切片进行免疫组织化学染色以识别蓝斑神经元。使用计算机成像程序对通过核的头尾范围的切片中的TH免疫反应性胞体进行计数。半合子小鼠中蓝斑神经元没有丧失。在第二个实验中，在2月龄和24月龄时检查纯合PDAPP和野生型小鼠。同样，纯合动物中没有与年龄相关的神经元丧失。然而，在蓝斑中投射到皮质和海马体的神经元所在部分，24月龄转基因动物中的神经元大小选择性减小。这些数据表明，在大量过表达Aβ肽后不会发生明显的蓝斑细胞丧失。然而，投射到含有与Aβ相关神经病理学的皮质和海马区域的蓝斑神经元群体的选择性大小减小意味着这些细胞可能受到逆行介导的应激。
