The levels of soluble versus insoluble brain Aβ distinguish Alzheimer's disease from normal and pathologic aging
The levels of soluble versus insoluble brain Aβ distinguish Alzheimer's disease from normal and pathologic aging
复制标题
DOI：
10.1006/exnr.1999.7085
复制
发表时间：
1999-08-01
影响因子：
5.3
通讯作者：
Lee, VMY
中科院分区：
文献类型：
--
作者：
Wang, J;Dickson, DW;Lee, VMY
Aβ多肽的丰度和溶解性是阿尔茨海默病(AD)淀粉样变性的关键决定因素。因此，我们用双抗体夹心酶联免疫吸附试验(ELISA)比较了AD患者与年龄匹配的正常和病理性衰老患者脑组织中总可溶性、不溶性和总Aβ1-40和Aβ1-42的水平。由于Aβ1-40和Aβ1-42的测定在很大程度上取决于夹心ELISA中使用的单抗的特异性，我首先证明了每一种抗体都是Aβ1-40或Aβ1-42的特异性抗体，并且这些多肽的水平不受脑提取液中淀粉样前体蛋白的影响。因此，这种夹心ELISA法使我们能够表明，皮质总可溶性和不溶性Aβ1-40和Aβ1-42的平均水平在AD组最高，在正常衰老时最低，在病理性衰老中居中。值得注意的是，与病理性老化的大脑相比，AD大脑中不溶性Aβ1-40的平均水平增加了20倍，而不溶性Aβ1-42的平均水平仅增加了2倍。此外，Aβ1-40和Aβ1-42在正常脑中所占比例最大(分别为50%和23%)，而在AD脑中最小(分别为2.7%和0.7%)，在病理性衰老脑中居中(分别为8%和0.8%)。因此，我们的数据表明病理性衰老是正常衰老和AD之间的一种过渡状态。更重要的是，我们的研究结果表明，脑内Aβ1-40和Aβ1-42从可溶池向不可溶池的渐进性转变以及不溶性Aβ1-40水平的显著增加在AD的发生和/或进展中起到了机械性的作用。(C)1999年学术出版社。
The abundance and solubility of A beta peptides are critical determinants of amyloidosis in Alzheimer's disease (AD). Hence, we compared levels of total soluble, insoluble, and total A beta 1-40 and A beta 1-42 in AD brains with those in age-matched normal and pathologic aging brains using a sandwich enzyme-linked immunosorbent assay (ELISA). Since the measurement of A beta 1-40 and A beta 1-42 depends critically on the specificity of the monoclonal antibodies used in the sandwich ELISA, me first demonstrated that each as say is specific for A beta 1-40 or A beta 1-42 and the levels of these peptides are not affected by the amyloid precursor protein in the brain extracts. Thus, this sandwich ELISA enabled us to show that the average levels of total cortical soluble and insoluble A beta 1-40 and A beta 1-42 were highest in AD, lowest in normal aging, and intermediate in pathologic aging. Remarkably, the average levels of insoluble A beta 1-40 were increased 20-fold while the average levels of insoluble A beta 1-42 were increased only 2-fold in the AD brains compared to pathologic aging brains. Further, the soluble pools of A beta 1-40 and A beta 1-42 were the largest fractions of total A beta in the normal brain (i.e., 50 and 23%, respectively), but they were the smallest in the AD brain (i.e., 2.7 and 0.7%, respectively) and intermediate (i.e., 8 and 0.8%, respectively) in pathologic aging brains. Thus, our data suggest that pathologic aging is a transition state between normal aging and AD. More importantly, our findings imply that a progressive shift of brain A beta 1-40 and A beta 1-42 from soluble to insoluble pools and a profound increase in the levels of insoluble A beta 1-40 plays mechanistic roles in the onset and/or progression of AD. (C) 1999 Academic Press.