Christensen Ditte Zerlang, Kraus Sophie Luise, Flohr Antonius, Cotel Marie-Caroline, Wirths Oliver, Bayer Thomas A
Division of Molecular Psychiatry and Alzheimer Ph.D. Graduate School, Department of Psychiatry, University of Goettingen, von-Siebold-Str. 5, 37075, Göttingen, Germany.
Acta Neuropathol. 2008 Dec;116(6):647-55. doi: 10.1007/s00401-008-0451-6. Epub 2008 Oct 31.
The accumulation of beta-amyloid (A beta) plaques and neurofibrillary tangles consisting of hyperphosphorylated tau protein are pathological features of Alzheimer's disease (AD) commonly modeled in mice using known human familial mutations; however, the loss of neurons also found to occur in AD is rarely observed in such models. The mechanism of neuron degeneration remains unclear but is of great interest as it is very likely an important factor for the onset of adverse memory deficits occurring in individuals with AD. The role of A beta in the neuronal degeneration is a matter of controversial debates. In the present study we investigated the impact of extracellular plaque A beta versus intraneuronal A beta on neuronal cell death. The thalamus and the frontal cortex of the APP/PS1KI mouse model were chosen for stereological quantification representing regions with plaques only (thalamus) or plaques as well as intraneuronal A beta (frontal cortex). A loss of neurons was found in the frontal cortex at the age of 6 months coinciding with the decrease of intraneuronal immunoreactivity, suggesting that the neurons with early intraneuronal A beta accumulation were lost. Strikingly, no neuron loss was observed in the thalamus despite the development of abundant plaque pathology with levels comparable to the frontal cortex. This study suggests that plaques have no effect on neuron death whereas accumulation of intraneuronal A beta may be an early transient pathological event leading to neuron loss in AD.
由过度磷酸化的tau蛋白组成的β-淀粉样蛋白（Aβ）斑块和神经原纤维缠结的积累是阿尔茨海默病（AD）的病理特征，通常在小鼠中使用已知的人类家族性突变来模拟；然而，在AD中也发现的神经元丢失在这类模型中很少被观察到。神经元变性的机制尚不清楚，但因其很可能是AD患者出现不良记忆缺陷发作的一个重要因素而备受关注。Aβ在神经元变性中的作用是一个有争议的话题。在本研究中，我们研究了细胞外斑块Aβ与神经元内Aβ对神经元细胞死亡的影响。选择APP/PS1KI小鼠模型的丘脑和额叶皮质进行体视学定量分析，分别代表仅含有斑块的区域（丘脑）或同时含有斑块和神经元内Aβ的区域（额叶皮质）。在6个月大时，额叶皮质发现有神经元丢失，这与神经元内免疫反应性的降低相一致，表明早期神经元内有Aβ积累的神经元丢失了。令人惊讶的是，尽管丘脑出现了大量与额叶皮质水平相当的斑块病理，但未观察到神经元丢失。这项研究表明，斑块对神经元死亡没有影响，而神经元内Aβ的积累可能是导致AD中神经元丢失的一个早期短暂病理事件。
