Persistent amyloidosis following suppression of Abeta production in a transgenic model of Alzheimer disease.
Persistent amyloidosis following suppression of Abeta production in a transgenic model of Alzheimer disease.
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DOI：
10.1371/journal.pmed.0020355
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发表时间：
2005-12
期刊：
影响因子：
15.8
通讯作者：
Borchelt DR
中科院分区：
文献类型：
--
作者：
Jankowsky JL;Slunt HH;Gonzales V;Savonenko AV;Wen JC;Jenkins NA;Copeland NG;Younkin LH;Lester HA;Younkin SG;Borchelt DR
从淀粉样前体蛋白(APP)中裂解淀粉样蛋白(Aβ，Aβ)的酶(分泌酶)一直是阿尔茨海默病治疗方法研究的重点。此前的预测是，减少大脑中Aβ的产生，即使在临床症状出现和相关病理发展之后，也将有助于受损组织的修复和淀粉样病变的移除。然而，还没有使用淀粉样蛋白病理的动物模型进行的长期研究来检验这一假说。我们已经建立了一个转基因小鼠模型，它在基因上模拟了分泌酶抑制剂治疗后预期的Aβ产生的停止。这些小鼠从一种可受多西环素调节的载体过度表达突变的APP。在正常情况下，APP的高水平表达会迅速引发暴发性淀粉样蛋白病变。我们发现，给予多西环素可以抑制转基因APP的表达95%以上，并将Aβ的产生减少到非转基因小鼠的水平。在这个模型中，抑制转基因Aβ的合成突然阻止了淀粉样蛋白病理的进展。然而，淀粉样蛋白沉积的形成和解聚似乎是不平衡的，因为斑块需要更长的时间才能分散而不是聚集。在Aβ沉积形成后，APP合成被抑制长达6个月的小鼠保留了相当大的淀粉样蛋白负荷，几乎没有主动清除的迹象。这项研究表明，转基因小鼠的淀粉样蛋白损伤是体内高度稳定的结构，分解速度很慢。我们的发现表明，阻止阿尔茨海默病患者Aβ的产生应该会阻止病理的进展，但早期治疗可能是必要的，因为似乎淀粉样沉积一旦形成，将需要额外的干预来清除。在过量表达淀粉样β蛋白的转基因小鼠中，通过四环素敏感开关关闭产生并不能减少淀粉样蛋白斑块的数量。
The proteases (secretases) that cleave amyloid-β (Aβ) peptide from the amyloid precursor protein (APP) have been the focus of considerable investigation in the development of treatments for Alzheimer disease. The prediction has been that reducing Aβ production in the brain, even after the onset of clinical symptoms and the development of associated pathology, will facilitate the repair of damaged tissue and removal of amyloid lesions. However, no long-term studies using animal models of amyloid pathology have yet been performed to test this hypothesis. We have generated a transgenic mouse model that genetically mimics the arrest of Aβ production expected from treatment with secretase inhibitors. These mice overexpress mutant APP from a vector that can be regulated by doxycycline. Under normal conditions, high-level expression of APP quickly induces fulminant amyloid pathology. We show that doxycycline administration inhibits transgenic APP expression by greater than 95% and reduces Aβ production to levels found in nontransgenic mice. Suppression of transgenic Aβ synthesis in this model abruptly halts the progression of amyloid pathology. However, formation and disaggregation of amyloid deposits appear to be in disequilibrium as the plaques require far longer to disperse than to assemble. Mice in which APP synthesis was suppressed for as long as 6 mo after the formation of Aβ deposits retain a considerable amyloid load, with little sign of active clearance. This study demonstrates that amyloid lesions in transgenic mice are highly stable structures in vivo that are slow to disaggregate. Our findings suggest that arresting Aβ production in patients with Alzheimer disease should halt the progression of pathology, but that early treatment may be imperative, as it appears that amyloid deposits, once formed, will require additional intervention to clear. In a transgenic mouse that overexpressed amyloid beta, turning off production via a tetracycline sensitive switch did not decrease the number of amyloid plaques present
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DOI：
10.1124/jpet.104.075408
发表时间：
2005-02-01
影响因子：
3.5
作者：
Barten, DM;Guss, VL;Felsenstein, KM
通讯作者：
Felsenstein, KM
DOI：
10.1016/s1050-3862(96)00167-2
发表时间：
1996-12-01
期刊：
GENETIC ANALYSIS-BIOMOLECULAR ENGINEERING
影响因子：
--
作者：
Borchelt, DR;Davis, J;Price, DL
通讯作者：
Price, DL
影响因子：
82.9
作者：
Backskai, BJ;Kajdasz, ST;Hyman, BT
通讯作者：
Hyman, BT
影响因子：
16.2
作者：
Hock, C;Konietzko, U;Nitsch, RM
通讯作者：
Nitsch, RM
影响因子：
2.9
作者：
HERMS, J;ZURMOHLE, U;SCHLINGENSIEPEN, KH
通讯作者：
SCHLINGENSIEPEN, KH