Amyloid-β1-40 Inhibits Amyloid-β1-42 Induced Activation of Cytoplasmic Phospholipase A2 and Synapse Degeneration
Amyloid-β1-40 Inhibits Amyloid-β1-42 Induced Activation of Cytoplasmic Phospholipase A2 and Synapse Degeneration
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DOI：
10.3233/jad-2010-100528
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发表时间：
2010-01-01
影响因子：
4
通讯作者：
Williams, Alun
中科院分区：
文献类型：
--
作者：
Bate, Clive;Williams, Alun
阿尔茨海默病（AD）的发病机制与淀粉样β（A β）肽的积累和突触的丧失有关。在AD诱导的突触变性模型中，A β（1-42）的加入减少了培养的皮层神经元中突触素的量。A β（1-42）也减少了荧光染料FM 1 -43进入突触再循环囊泡的摄取，这是突触功能的一种测量。我们报告说，预先混合A β（1-40）和A β（1-42）显著降低了A β（1- 42）对突触的影响;它增加了突触囊泡的再循环和突触体素的含量。这些结果与A β（1-40）与A β（1-42）形成寡聚体的报告一致，并且这些寡聚体的毒性低于单独的A β（1-42）。相反，A β（1-40）的加入不影响由朊病毒衍生肽PrP 82 -146诱导的突触变性。A β（1-40）的加入减少了A β（1-42）诱导的突触内细胞质磷脂酶A（2）（cPLA（2））的激活，这与A β（1-42）诱导的突触变性是由突触cPLA（2）的异常激活介导的假设一致。这些观察结果提出了一种可能性，即大脑中产生的A β（1-40）的量在确定A β（1-42）的突触损伤作用以及可能在AD早期阶段观察到的认知丧失方面至关重要。
The pathogenesis of Alzheimer's disease (AD) is associated with the accumulation of amyloid-beta (A beta) peptides and the loss of synapses. The addition of A beta(1-42) reduced the amount of synaptophysin in cultured cortical neurons in a model of AD-induced synapse degeneration. A beta(1-42) also reduced the uptake of the fluorescent dye FM1-43 into synaptic recycling vesicles, a measure of synaptic function. We report that pre-mixing A beta(1-40) with A beta(1-42) significantly reduced the effects of A beta(1-42) on synapses; it increased both synaptic vesicle recycling and synaptophysin content. These results are consistent with reports that A beta(1-40) forms oligomers with A beta(1-42) and that these are less toxic than A beta(1-42) alone. In contrast, the addition of A beta(1-40) did not affect the synapse degeneration induced by the prion-derived peptide PrP82-146. The addition of A beta(1-40) reduced A beta(1-42) induced activation of cytoplasmic phospholipase A(2) (cPLA(2)) within synapses consistent with the hypothesis that A beta(1-42) induced synapse degeneration is mediated by aberrant activation of synaptic cPLA(2). Such observations raise the possibility that the amount of A beta(1-40) produced within the brain is critical in determining the synapse damaging effects of A beta(1-42) and possibly the cognitive loss seen during the early stages of AD.