van de Nes J A P, Nafe R, Schlote W
Institute of Pathology and Neuropathology, University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany.
Brain Res. 2008 Jun 5;1213:152-65. doi: 10.1016/j.brainres.2008.03.043. Epub 2008 Apr 1.
In Alzheimer's disease (AD), cortical neurons develop neurofibrillary tangles (NFTs) consisting of hyperphosphorylated tau. The neurons eventually die. There are some hints that cortical neurons may also degenerate without the development of cytoskeletal changes. We investigated this possibility by comparing changes in APP staining and neuronal size with respect to the presence or absence of hyperphosphorylated tau. Adjacent sections of the medial temporal neocortex (Brodmann's area 22) of 5 male AD patients aged 60-88 years (Braak V-VI) and 5 age-matched male non-demented control subjects were i) stained with a modified Bielschowsky silver method in order to reveal NFTs and 'ghost' tangles, ii) single-stained with anti-APP, and iii) double-labeled with anti-APP and AT8. Anti-APP is directed against the beta-amyloid precursor protein and stains virtually all perikarya and proximal neurites of the cortical neurons. AT8 stains pre-tangles, NFTs and extracellular 'ghost' tangles due to the recognition of hyperphosphorylated tau. The study was focused on the supragranular cortical layers II-III, since these layers can be clearly delineated from the adjacent molecular and granular cell layers. The results showed that i) APP staining intensity in neurons was variable in the AD cortex, being clearly different from the invariably intense neuronal staining in all controls. Reduced cytoplasmic APP staining was observed, particular in small neurons, while lack of anti-APP staining in proximal neurites, too, was associated with AD. In addition, ii) cross-sectional area measurement on anti-APP-stained neurons revealed that in AD, as compared to controls, a clear decrease in the number of mainly large-sized neurons (>150 microm2) was accompanied by a significant increase in the percentage of neurons in the smaller size classes, indicating that many large-sized neurons became smaller in AD. iii) Reduced APP staining and decreased neuronal size were not necessarily associated with the presence or absence of hyperphosphorylated tau in these cells. iv) Twenty-six percent of the neurons contained hyperphosphorylated tau, while the level of NFT-related neuronal loss was low in AD. The present study suggests that non-tau based neuronal degeneration is a major phenomenon in the AD neocortex.
在阿尔茨海默病（AD）中，皮质神经元会形成由过度磷酸化tau蛋白组成的神经原纤维缠结（NFTs）。这些神经元最终会死亡。有一些迹象表明，皮质神经元也可能在没有细胞骨架变化的情况下发生退化。我们通过比较APP染色和神经元大小相对于过度磷酸化tau蛋白的有无的变化来研究这种可能性。对5名年龄在60 - 88岁的男性AD患者（Braak V - VI期）和5名年龄匹配的男性非痴呆对照受试者的内侧颞叶新皮质（布罗德曼22区）的相邻切片进行了如下处理：i）用改良的 Bielschowsky 银染法染色以显示NFTs和“幽灵”缠结；ii）用抗APP单染；iii）用抗APP和AT8双标。抗APP针对β - 淀粉样前体蛋白，几乎能染所有皮质神经元的胞体和近端神经突。AT8由于能识别过度磷酸化的tau蛋白，可染前缠结、NFTs和细胞外“幽灵”缠结。该研究聚焦于颗粒上层皮质II - III层，因为这些层可与相邻的分子层和颗粒细胞层清晰区分。结果显示：i）AD皮质中神经元的APP染色强度各异，与所有对照中神经元始终强烈的染色明显不同。观察到胞质APP染色减少，尤其是在小神经元中，而近端神经突中抗APP染色缺失也与AD相关。此外，ii）对抗APP染色的神经元进行横截面积测量发现，与对照相比，AD中主要大尺寸神经元（>150平方微米）数量明显减少，同时小尺寸神经元百分比显著增加，表明AD中有许多大尺寸神经元变小。iii）APP染色减少和神经元尺寸减小不一定与这些细胞中过度磷酸化tau蛋白的有无相关。iv）26%的神经元含有过度磷酸化的tau蛋白，而AD中与NFT相关的神经元损失水平较低。本研究表明，非tau蛋白依赖性神经元退化是AD新皮质中的主要现象。
