The potential for β-structure in the repeat domain of Tau protein determines aggregation, synaptic decay, neuronal loss, and coassembly with endogenous Tau in inducible mouse models of tauopathy
The potential for β-structure in the repeat domain of Tau protein determines aggregation, synaptic decay, neuronal loss, and coassembly with endogenous Tau in inducible mouse models of tauopathy
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DOI：
10.1523/jneurosci.2824-07.2008
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发表时间：
2008-01-16
影响因子：
5.3
通讯作者：
Mandelkow, Eva-Maria
中科院分区：
文献类型：
--
作者：
Mocanu, Maria-Magdalena;Nissen, Astrid;Mandelkow, Eva-Maria
我们描述了两个新的转基因小鼠品系，用于研究阿尔茨海默病相关Tau蛋白的病理变化。它们基于携带FTDP 17（与17号染色体相关的额颞叶痴呆和帕金森综合征）突变Δ K280（Tau（RD）/Δ K280）或Δ K280加上六肽基序中的两个脯氨酸突变（TauRD/Δ K280/I277P/I308P）的人Tau的四重复结构域的可调控表达。Delta K280突变加速聚集（"促聚集突变体"），而脯氨酸突变在体外和细胞模型中抑制Tau聚集（"抗聚集突变体"）。诱导型转基因表达由前脑特异性CaMKII α（钙/钙调蛋白依赖性蛋白激酶II α）启动子驱动。早在基因表达后2 - 3个月，即使在低表达（70%的内源性小鼠Tau）下，促聚集突变体也导致Tau聚集体和缠结。抗聚集突变体即使在基因表达22个月后也不聚集。两种突变体均显示体树突区室中Tau的错误分选和重复结构域中的过度磷酸化[KXGS基序，激酶MARK（微管亲和力调节激酶）的靶标]。这表明这些变化与Tau表达有关，而不是聚集。从基因表达的5个月开始，前聚集突变体导致星形胶质细胞增生、突触和神经元的损失，认为Tau毒性与聚集有关。值得注意的是，人前聚集突变体Tau（RD）与小鼠Tau共聚集，伴随多个位点的错误分选和过度磷酸化。当关闭促聚集TauRD的表达时，可溶性和聚集的外源性Tau（RD）在1.5个月内消失。然而，小鼠Tau的缠结、过度磷酸化和错误分选仍然存在，这表明一旦病理构象和聚集被前聚集Tau种类诱导，聚集的野生型Tau的寿命延长。
We describe two new transgenic mouse lines for studying pathological changes of Tau protein related to Alzheimer's disease. They are based on the regulatable expression of the four-repeat domain of human Tau carrying the FTDP17 (frontotemporal dementia and parkinsonism linked to chromosome 17) mutation Delta K280 (Tau(RD)/Delta K280), or the Delta K280 plus two proline mutations in the hexapeptide motifs (TauRD/Delta K280/I277P/I308P). The Delta K280 mutation accelerates aggregation ("proaggregation mutant"), whereas the proline mutations inhibit Tau aggregation in vitro and in cell models ("antiaggregation mutant"). The inducible transgene expression was driven by the forebrain-specific CaMKII alpha(calcium/calmodulin-dependent protein kinase II alpha) promoter. The proaggregation mutant leads to Tau aggregates and tangles as early as 2-3 months after gene expression, even at low expression (70% of endogenous mouse Tau). The antiaggregation mutant does not aggregate even after 22 months of gene expression. Both mutants show missorting of Tau in the somatodendritic compartment and hyperphosphorylation in the repeat domain [ KXGS motifs, targets of the kinase MARK(microtubule affinity regulating kinase)]. This indicates that these changes are related to Tau expression rather than aggregation. The proaggregation mutant causes astrogliosis, loss of synapses and neurons from 5 months of gene expression onward, arguing that Tau toxicity is related to aggregation. Remarkably, the human proaggregation mutant Tau(RD) coaggregates with mouse Tau, coupled with missorting and hyperphosphorylation at multiple sites. When expression of proaggregation TauRD is switched off, soluble and aggregated exogenous Tau(RD) disappears within 1.5 months. However, tangles of mouse Tau, hyperphosphorylation, and missorting remain, suggesting an extended lifetime of aggregated wild-type Tau once a pathological conformation and aggregation is induced by a proaggregation Tau species.