Suppression of amyloid deposition leads to long-term reductions in Alzheimer's pathologies in Tg2576 mice.
Suppression of amyloid deposition leads to long-term reductions in Alzheimer's pathologies in Tg2576 mice.
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DOI：
10.1523/jneurosci.4560-08.2009
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发表时间：
2009-04-15
期刊：
影响因子：
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通讯作者：
Morgan D
中科院分区：
文献类型：
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作者：
Karlnoski RA;Rosenthal A;Kobayashi D;Pons J;Alamed J;Mercer M;Li Q;Gordon MN;Gottschall PE;Morgan D
在淀粉样前体蛋白(APP)的淀粉样沉积模型中，淀粉样沉积的数量随着小鼠年龄的增加而增加。在第一个近似值中，淀粉样蛋白积累的程度可能反映了随着时间积累的产量超过清除的微小过剩，或者，或者，替代地，反映了该年龄的稳定状态平衡，反映了瞬时的生产超过清除，这随着生物体的年龄而增加。为了区分这些选项，我们用抗Aü抗体2H6可逆地抑制了Tg2576小鼠的淀粉样蛋白沉积，从8mo开始，就在第一批组织学沉积可以识别之前。六个月后，我们停止了抑制，并在接下来的3个月里监测了对照组APP小鼠和被抑制APP小鼠的淀粉样蛋白积累的进展。蓄积假说将预测抑制组和对照组小鼠在14-17mo之间淀粉样蛋白的速率相似，而平衡假说将预测抑制组小鼠淀粉样蛋白的增加会更快，可能完全赶上对照组。结果有力地支持了积聚假说，没有证据表明被抑制的小鼠像平衡模型预测的那样赶上了对照小鼠。如果说有什么不同的话，那就是受到抑制的APP小鼠的增长速度比对照小鼠慢，这表明在确定淀粉样蛋白沉积的程度时，缓慢的种子机制可能先于快速的纤维形成。
In amyloid precursor protein (APP) models of amyloid deposition, the amount of amyloid deposits increase with mouse age. At a first approximation, the extent of amyloid accumulation may reflect either small excesses of production over clearance that accumulate over time, or, alternatively indicate the a steady state equilibrium at that age, reflecting the instantaneous excess of production over clearance, which increases as the organism ages. To discriminate between these options, we reversibly suppressed amyloid deposition in Tg2576 mice with the anti-Aß antibody 2H6, starting at 8 mo, just before the first histological deposits can be discerned. Six months later, we stopped the suppression and monitored the progression of amyloid accumulation in control APP mice and suppressed APP mice over the next 3 months. The accumulation hypothesis would predict that the rate of amyloid from 14 to 17 mo would be similar in the suppressed and control mice, while the equilibrium hypothesis would predict that the increase would be faster in the suppressed group, possibly catching up completely with the control mice. The results strongly support the accumulation hypothesis, with no evidence of the suppressed mice catching up with the control mice as predicted by equilibrium models. If anything, there was a slower rate of increase in the suppressed APP mice than the control mice, suggesting that a slow seeding mechanism likely precedes a rapid fibrillogenesis in determining the extent of amyloid deposition.