Transient intraneuronal Aβ rather than extracellular plaque pathology correlates with neuron loss in the frontal cortex of APP/PS1KI mice
Transient intraneuronal Aβ rather than extracellular plaque pathology correlates with neuron loss in the frontal cortex of APP/PS1KI mice
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DOI：
10.1007/s00401-008-0451-6
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发表时间：
2008-12-01
影响因子：
12.7
通讯作者：
Bayer, Thomas A.
中科院分区：
文献类型：
--
作者：
Christensen, Ditte Zerlang;Kraus, Sophie Luise;Bayer, Thomas A.
β-淀粉样蛋白 (Aβ) 斑块的积累和由过度磷酸化 tau 蛋白组成的神经原纤维缠结是阿尔茨海默病 (AD) 的病理特征，通常使用已知的人类家族突变在小鼠中建模；然而，在 AD 中也发现神经元丢失，但在此类模型中很少观察到。神经元变性的机制尚不清楚，但引起了人们极大的兴趣，因为它很可能是 AD 患者出现不良记忆缺陷的重要因素。 Aβ 在神经元变性中的作用是一个有争议的问题。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层进行体视定量，代表仅具有斑块（丘脑）或斑块以及神经元内 Aβ（额叶皮层）的区域。 6 个月大时，在额叶皮层发现神经元丢失，同时神经元内免疫反应性下降，这表明早期神经元内 Aβ 积累的神经元丢失了。引人注目的是，尽管出现了丰富的斑块病理，其水平与额叶皮层相当，但在丘脑中没有观察到神经元损失。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 中神经元损失的早期短暂病理事件。
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.