Plasma levels of aβ42 and aβ40 in Alzheimer patients during treatment with the acetylcholinesterase inhibitor tacrine
Plasma levels of aβ42 and aβ40 in Alzheimer patients during treatment with the acetylcholinesterase inhibitor tacrine
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DOI：
10.1159/000063605
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发表时间：
2002-01-01
影响因子：
2.4
通讯作者：
Younkin, S
中科院分区：
文献类型：
--
作者：
Basun, H;Nilsberth, C;Younkin, S
淀粉样前体蛋白 (APP) 加工失调导致淀粉样β-肽 (Abeta) 产量增加，被认为是阿尔茨海默病 (AD) 的关键致病事件。有人提出，刺激毒蕈碱 M-1 受体亚型会影响 APP 加工并导致 Abeta 浓度变化。为了检验胆碱酯酶抑制剂治疗可以改变血浆中 Abeta 水平的假设，我们在他克林治疗前以及治疗第 2 周和第 6 周时测量了 AD 受试者的 Abeta42 和 Abeta40 血浆水平。与基线水平相比，他克林治疗在给药 2 周或 6 周时对血浆 Abeta42 和 Abeta40 没有统计学上的显着影响。血浆 Abeta42 和 Abeta40 水平显示个体间差异较大，但同一患者在 3 个样本间隔内差异较小。用他克林治疗2周后，他克林浓度与Abeta42（r = -0.64；p = 0.01）和Abeta40（r = -0.55；p = 0.04）水平之间存在很强的负相关性。然而，6周后，他克林的血浆浓度与血浆中的Abeta42（r = 0.33；p = 0.34）或Abeta40（r = -0.22；p = 0.54）水平之间没有相关性。使用乙酰胆碱酯酶抑制剂治疗两周后，我们发现较高的药物浓度和较低的β-淀粉样蛋白水平之间存在相关性。这可能表明 a-裂解增加对 APP 代谢有影响。但药物治疗6周后，药物对β-淀粉样蛋白浓度没有明显影响。这一发现可能表明代偿机制在 6 周时就已经开始，并且预计抑制乙酰胆碱酯酶不会对 AD 的关键病理特征产生长期影响。版权所有 (C) 2002 S. Karger AG，巴塞尔。
Deregulation of amyloid precursor protein (APP) processing with increased production of amyloid beta-peptide (Abeta) is considered to be a key pathogenic event in Alzheimer's disease (AD). It has been suggested that stimulation of the muscarinic M-1 receptor subtype affects APP processing and leads to a change in Abeta concentration. To test the hypothesis that treatment with a cholinesterase inhibitor could change the levels of Abeta in plasma, we measured Abeta42 and Abeta40 plasma levels in AD subjects before tacrine treatment and at weeks 2 and 6 of treatment. Treatment with tacrine had no statistically significant effect on plasma Abeta42 and Abeta40 either at 2 weeks or at 6 weeks of administration compared to baseline levels. Plasma Abeta42 and Abeta40 levels showed large subject-to-subject variation but small variation within the same patient over the 3-sample interval. After 2 weeks of treatment with tacrine, there was a strong negative correlation between tacrine concentration and levels of Abeta42 (r = -0.64; p = 0.01) and Abeta40 (r = -0.55; p = 0.04). However, after 6 weeks there was no correlation between plasma concentrations of tacrine and Abeta42 (r = 0.33; p = 0.34) or Abeta40 (r = -0.22; p = 0.54) levels in plasma. After 2 weeks of treatment with an acetylcholinesterase inhibitor, we found a correlation between higher drug concentrations and lower beta-amyloid levels. This might indicate an effect on APP metabolism with an increased a-cleavage. But after 6 weeks of drug treatment, there was no obvious drug effect on beta-amyloid concentrations. This finding may indicate that compensatory mechanisms have started at 6 weeks and that no long-term effect on key pathological features in AD is to be expected by an inhibition of acetylcholinesterase. Copyright (C) 2002 S. Karger AG, Basel.