Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China.
J Alzheimers Dis. 2011;26(2):299-313. doi: 10.3233/JAD-2011-102061.
Intracellular tau aggregates composed of neurofibrillary tangles (NFTs) are a defining feature of Alzheimer's disease (AD). Increased expression of heme oxygenase-1 (HO-1) is a common phenomenon in AD. Interestingly, the spatial distribution of HO-1 expression is essentially identical to that of pathological accumulation of tau in AD. In this study, we developed a new transgenic mouse overexpressing HO-1, called CAG-HO-1 Tg mice, to explore the relationship between HO-1 and tau aggregation. In this model, we found that long-term overexpression of HO-1 significantly promoted tau aggregation in brain, by analyzing changes in morphology and insoluble tau expression levels. Moreover, our research provides the first in vivo evidence that HO-1 can enhance iron loading and tau (Ser199/202/396) phosphorylation in brains of transgenic mice. Cellular evidence indicates that HO-1 can induce the phosphorylation of tau through iron accumulation in Neuro2a cells stably transfected with HO-1. Our data suggest that long-term overexpression of HO-1 can promote tau aggregation. This mechanism involves excessive iron production mediated by HO-1 overexpression, which induces tau phosphorylation. Our results provide a potential pathway for the pathogenesis of tauopathies, which remains largely unknown.
细胞内由神经纤维缠结（NFTs）组成的 tau 聚集体是阿尔茨海默病（AD）的一个明确特征。血红素加氧酶-1（HO-1）的表达增加是 AD 的常见现象。有趣的是，HO-1 表达的空间分布与 AD 中 tau 的病理性积累基本相同。在这项研究中，我们开发了一种过表达 HO-1 的新型转基因小鼠，称为 CAG-HO-1 Tg 小鼠，以探索 HO-1 和 tau 聚集之间的关系。在该模型中，我们通过分析形态变化和不溶性 tau 表达水平，发现 HO-1 的长期过表达显著促进了大脑中的 tau 聚集。此外，我们的研究提供了第一个体内证据，表明 HO-1 可以增强转基因小鼠大脑中的铁负荷和 tau（Ser199/202/396）磷酸化。细胞证据表明，HO-1 可以通过在稳定转染 HO-1 的 Neuro2a 细胞中积累铁来诱导 tau 的磷酸化。我们的数据表明，HO-1 的长期过表达可以促进 tau 聚集。这种机制涉及由 HO-1 过表达介导的过量铁产生，从而诱导 tau 磷酸化。我们的结果为 tau 病发病机制的一个潜在途径提供了依据，而 tau 病的发病机制在很大程度上尚不清楚。
