Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Rome, Italy.
PLoS One. 2010 Nov 15;5(11):e13989. doi: 10.1371/journal.pone.0013989.
Lifelong latent infections of the trigeminal ganglion by the neurotropic herpes simplex virus type 1 (HSV-1) are characterized by periodic reactivation. During these episodes, newly produced virions may also reach the central nervous system (CNS), causing productive but generally asymptomatic infections. Epidemiological and experimental findings suggest that HSV-1 might contribute to the pathogenesis of Alzheimer's disease (AD). This multifactorial neurodegenerative disorder is related to an overproduction of amyloid beta (Aβ) and other neurotoxic peptides, which occurs during amyloidogenic endoproteolytic processing of the transmembrane amyloid precursor protein (APP). The aim of our study was to identify the effects of productive HSV-1 infection on APP processing in neuronal cells. We found that infection of SH-SY5Y human neuroblastoma cells and rat cortical neurons is followed by multiple cleavages of APP, which result in the intra- and/or extra-cellular accumulation of various neurotoxic species. These include: i) APP fragments (APP-Fs) of 35 and 45 kDa (APP-F35 and APP-F45) that comprise portions of Aβ; ii) N-terminal APP-Fs that are secreted; iii) intracellular C-terminal APP-Fs; and iv) Aβ(1-40) and Aβ(1-42). Western blot analysis of infected-cell lysates treated with formic acid suggests that APP-F35 may be an Aβ oligomer. The multiple cleavages of APP that occur in infected cells are produced in part by known components of the amyloidogenic APP processing pathway, i.e., host-cell β-secretase, γ-secretase, and caspase-3-like enzymes. These findings demonstrate that HSV-1 infection of neuronal cells can generate multiple APP fragments with well-documented neurotoxic potentials. It is tempting to speculate that intra- and extracellular accumulation of these species in the CNS resulting from repeated HSV-1 reactivation could, in the presence of other risk factors, play a co-factorial role in the development of AD.
单纯疱疹病毒 1 型（HSV-1）对三叉神经节的终身潜伏感染的特征是周期性再激活。在此期间，新产生的病毒粒子也可能到达中枢神经系统（CNS），导致产生但通常无症状的感染。流行病学和实验发现表明，HSV-1 可能有助于阿尔茨海默病（AD）的发病机制。这种多因素神经退行性疾病与淀粉样β（Aβ）和其他神经毒性肽的过度产生有关，这些肽在跨膜淀粉样前体蛋白（APP）的淀粉样蛋白内切酶加工过程中发生。我们的研究目的是确定产生活性 HSV-1 感染对神经元细胞中 APP 加工的影响。我们发现，感染 SH-SY5Y 人神经母细胞瘤细胞和大鼠皮质神经元后，APP 会发生多次切割，导致各种神经毒性物质在细胞内和/或细胞外积累。这些包括：i）包含 Aβ部分的 35 和 45 kDa 的 APP 片段（APP-F35 和 APP-F45）；ii）分泌的 N 端 APP-Fs；iii）细胞内 C 端 APP-Fs；和 iv）Aβ（1-40）和 Aβ（1-42）。用甲酸处理感染细胞裂解物的 Western blot 分析表明，APP-F35 可能是 Aβ 寡聚物。感染细胞中发生的 APP 多次切割部分是由淀粉样蛋白 APP 加工途径的已知成分产生的，即宿主细胞 β-分泌酶、γ-分泌酶和半胱天冬酶-3 样酶。这些发现表明，神经元细胞中的 HSV-1 感染可以产生具有明确神经毒性潜力的多种 APP 片段。人们不禁推测，由于 HSV-1 反复再激活而导致 CNS 中这些物质的细胞内和细胞外积累，如果存在其他风险因素，可能在 AD 的发展中发挥共同作用。
