Alzheimer disease models and human neuropathology: similarities and differences.
Alzheimer disease models and human neuropathology: similarities and differences.
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DOI：
10.1007/s00401-007-0312-8
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发表时间：
2008-01
影响因子：
12.7
通讯作者：
Delatour B
中科院分区：
文献类型：
--
作者：
Duyckaerts C;Potier MC;Delatour B
动物模型旨在复制阿尔茨海默病的症状、病变或病因。许多小鼠转基因系现在已经成功地部分复制了其病变：Aβ肽的细胞外沉积和tau蛋白的细胞内积累。突变的人APP转基因导致Aβ肽沉积，其与人老年斑的Aβ肽相似但不相同。淀粉样血管病很常见。除Aβ沉积外，还观察到轴突营养不良和树突改变。所有的突变都会导致Aβ 42水平的增加，除了北极突变，它改变了Aβ序列本身。单独过表达野生型APP（如在人类21三体的小鼠模型中）不会导致大多数小鼠系中的Aβ沉积。双（APP ×突变的PS1）转基因小鼠的病变发展较早。已经产生了BACE 1被敲除或过表达的转基因小鼠，以及Aβ的主要降解酶脑啡肽酶表达改变的品系。APP转基因小鼠提出了有关神经元丢失、Aβ在神经元细胞体中积累、炎症和神经胶质增生以及树突状改变机制的新问题。它们使人们对变化的动力学有了一些了解。已发现症状、病变和Aβ寡聚体增加之间的联系难以阐明。神经元缠结仅存在于在鼠tau −/−背景上过表达突变tau或人tau的小鼠品系中。三重转基因模型（突变的APP、PS1和tau）概括了AD中观察到的变化，但其生理相关性可能需要讨论。已经测试了许多Aβ或tau蓄积的调节剂。一个转基因动物模型至少可以从三个层次（症状、病变、病因）进行分析，并提出了一个阅读检索表来总结这一分析。
Animal models aim to replicate the symptoms, the lesions or the cause(s) of Alzheimer disease. Numerous mouse transgenic lines have now succeeded in partially reproducing its lesions: the extracellular deposits of Aβ peptide and the intracellular accumulation of tau protein. Mutated human APP transgenes result in the deposition of Aβ peptide, similar but not identical to the Aβ peptide of human senile plaque. Amyloid angiopathy is common. Besides the deposition of Aβ, axon dystrophy and alteration of dendrites have been observed. All of the mutations cause an increase in Aβ 42 levels, except for the Arctic mutation, which alters the Aβ sequence itself. Overexpressing wild-type APP alone (as in the murine models of human trisomy 21) causes no Aβ deposition in most mouse lines. Doubly (APP × mutated PS1) transgenic mice develop the lesions earlier. Transgenic mice in which BACE1 has been knocked out or overexpressed have been produced, as well as lines with altered expression of neprilysin, the main degrading enzyme of Aβ. The APP transgenic mice have raised new questions concerning the mechanisms of neuronal loss, the accumulation of Aβ in the cell body of the neurons, inflammation and gliosis, and the dendritic alterations. They have allowed some insight to be gained into the kinetics of the changes. The connection between the symptoms, the lesions and the increase in Aβ oligomers has been found to be difficult to unravel. Neurofibrillary tangles are only found in mouse lines that overexpress mutated tau or human tau on a murine tau −/− background. A triply transgenic model (mutated APP, PS1 and tau) recapitulates the alterations seen in AD but its physiological relevance may be discussed. A number of modulators of Aβ or of tau accumulation have been tested. A transgenic model may be analyzed at three levels at least (symptoms, lesions, cause of the disease), and a reading key is proposed to summarize this analysis.
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影响因子：
5.3
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