Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
Mol Med. 2012 Mar 27;18(1):178-85. doi: 10.2119/molmed.2011.00366.
Hereditary cerebral hemorrhage with amyloidosis-Dutch type is a disorder associated with a missense mutation (E693Q) in the β-amyloid (Aβ)-coding region of the amyloid precursor protein (APP). This familial disease is characterized by cognitive deficits secondary to intracerebral hemorrhage and, in some cases, progressive Alzheimer's disease (AD)-like dementia. Although this mutation was the first ever reported in the human APP gene, little is known about the molecular mechanisms underlying the direct toxic effects of this mutated Aβ on central neurons. In the present study, we assessed the role of calpain-mediated toxicity in such effects using an AD primary culture model system. Our results showed that Dutch mutant Aβ (E22Q) induced calpain-mediated cleavage of dynamin 1 and a significant decrease in synaptic contacts in mature hippocampal cultures. These synaptic deficits were similar to those induced by wild-type (WT) Aβ. In contrast, calpain-mediated tau cleavage leading to the generation of a 17-kDa neurotoxic fragment, as well as neuronal death, were significantly reduced in E22Q Aβ-treated neurons when compared with WT Aβ-treated ones. This complex regulation of the calpain-mediated toxicity pathway by E22Q Aβ could have some bearing in the pathobiology of this familial AD form.
遗传性脑淀粉样血管病伴荷兰型是一种与β-淀粉样蛋白（Aβ）编码区域淀粉样前体蛋白（APP）中的错义突变（E693Q）相关的疾病。这种家族性疾病的特征是由于脑出血导致认知能力下降，在某些情况下还会出现进行性阿尔茨海默病（AD）样痴呆。尽管这种突变是首次在人类 APP 基因中报道的，但对于这种突变的 Aβ对中枢神经元的直接毒性作用的分子机制知之甚少。在本研究中，我们使用 AD 原代培养模型系统评估了钙蛋白酶介导的毒性在此类作用中的作用。我们的结果表明，荷兰突变型 Aβ（E22Q）诱导了动力蛋白 1的钙蛋白酶介导的切割，并导致成熟海马培养物中突触接触的显著减少。这些突触缺陷与野生型（WT）Aβ诱导的相似。相比之下，E22Q Aβ处理的神经元中，钙蛋白酶介导的 tau 切割导致产生 17kDa 的神经毒性片段以及神经元死亡的程度明显低于 WT Aβ 处理的神经元。E22Q Aβ对钙蛋白酶介导的毒性途径的这种复杂调节可能与这种家族性 AD 形式的病理生物学有关。
