Jankowsky Joanna L, Slunt Hilda H, Gonzales Victoria, Savonenko Alena V, Wen Jason C, Jenkins Nancy A, Copeland Neal G, Younkin Linda H, Lester Henry A, Younkin Steven G, Borchelt David R
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
PLoS Med. 2005 Dec;2(12):e355. doi: 10.1371/journal.pmed.0020355. Epub 2005 Nov 15.
The proteases (secretases) that cleave amyloid-beta (Abeta) 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 Abeta 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 Abeta 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 Abeta production to levels found in nontransgenic mice. Suppression of transgenic Abeta 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 Abeta 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 Abeta 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.
从淀粉样前体蛋白（APP）上切割淀粉样β（Aβ）肽的蛋白酶（分泌酶）一直是阿尔茨海默病治疗研发中大量研究的焦点。据预测，即使在临床症状出现及相关病理发展之后，减少大脑中Aβ的产生也将有助于受损组织的修复和淀粉样病变的清除。然而，尚未进行使用淀粉样病理动物模型的长期研究来验证这一假设。
我们构建了一种转基因小鼠模型，该模型在基因上模拟了分泌酶抑制剂治疗预期的Aβ产生停滞。这些小鼠从可由强力霉素调控的载体中过表达突变型APP。在正常条件下，APP的高水平表达会迅速诱发暴发性淀粉样病理。我们表明，给予强力霉素可抑制转基因APP表达超过95%，并将Aβ产生减少至非转基因小鼠中的水平。在该模型中抑制转基因Aβ合成可突然停止淀粉样病理的进展。然而，淀粉样沉积物的形成和解聚似乎处于不平衡状态，因为斑块分散所需的时间远比组装所需的时间长得多。在Aβ沉积物形成后APP合成被抑制长达6个月的小鼠仍保留相当数量的淀粉样负荷，几乎没有主动清除的迹象。
本研究表明，转基因小鼠中的淀粉样病变在体内是高度稳定的结构，解聚缓慢。我们的研究结果表明，在阿尔茨海默病患者中阻止Aβ产生应能停止病理进展，但早期治疗可能至关重要，因为一旦形成淀粉样沉积物，似乎需要额外干预才能清除。
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