Dolev Iftach, Michaelson Daniel M
The Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
J Alzheimers Dis. 2006 Nov;10(2-3):291-301. doi: 10.3233/jad-2006-102-313.
The amyloid-beta (Abeta) peptide is a major constituent of the brain senile plaques that characterize Alzheimer's disease (AD). Converging observations led to the formulation of the amyloid hypothesis whereby the accumulation of soluble aggregates and insoluble Abeta deposits is the primary event in AD pathogenesis. Furthermore, the apoE4 isoform of apolipoprotein E, a major prevalent genetic risk factor of AD, is associated with increased Abeta deposition. To investigate the initial stages of the amyloid cascade in vivo and how this is affected by apoE4, we studied the effects of prolonged inhibition and subsequent reactivation of the Abeta-degrading enzyme, neprilysin, on aggregation and deposition of Abeta in apoE transgenic and control mice. The results revealed that Abeta deposition in vivo is initiated by aggregation of Abeta42, which is followed by reversible deposition of both Abeta42 and Abeta40, along with growth of the deposits, and by their subsequent irreversible fibrillization. The initiation of Abeta42 deposition is accelerated isoform-specifically by apoE4, whereas the growth and dissolution of the Abeta deposits as well as their fibrillization are similarly stimulated by the various apoE isoforms. Interestingly, Abeta deposition was associated with increased gliosis, which may reflect early pathological interactions of beta with the brain's parenchyma.
β-淀粉样蛋白（Aβ）肽是阿尔茨海默病（AD）特征性脑老年斑的主要成分。越来越多的观察结果促使人们提出了淀粉样蛋白假说，即可溶性聚集体和不溶性Aβ沉积物的积累是AD发病机制中的主要事件。此外，载脂蛋白E的ApoE4亚型是AD的主要常见遗传风险因素，与Aβ沉积增加有关。为了研究体内淀粉样蛋白级联反应的初始阶段以及ApoE4如何影响这一过程，我们研究了长时间抑制并随后重新激活Aβ降解酶中性内肽酶对ApoE转基因小鼠和对照小鼠中Aβ聚集和沉积的影响。结果显示，体内Aβ沉积由Aβ42聚集引发，随后是Aβ42和Aβ40的可逆沉积以及沉积物的生长，随后是它们的不可逆纤维化。ApoE4以亚型特异性方式加速Aβ42沉积的起始，而Aβ沉积物的生长、溶解及其纤维化受到各种ApoE亚型的类似刺激。有趣的是，Aβ沉积与胶质细胞增生增加有关，这可能反映了β与脑实质的早期病理相互作用。
