摘要
老年痴呆,又称为阿尔茨海默病(Alzheimer's Disease, AD)是一种进行性发展的神经退行性疾病,其临床表现为认知能力下降、记忆功能降低甚至丧失。随着老龄社会的到来,患阿尔茨海默病的病人会越来越多,给社会和家庭带来沉重的经济负担。AD病人脑中两大病理学特征是：神经元外由Aβ短肽形成的老年斑(Senile plaques,SP)的沉积；神经元内神经纤维缠结(Neurofibrillary tangles, NFTs)的聚集。神经纤维缠结是由过度磷酸化的tau蛋白构成。并且研究发现,由过度磷酸化的tau蛋白形成的NTFs的数量和AD病人的临床痴呆程度成正相关。
内质网(Endoplasmic reticulum, ER)是真核细胞中最重要的细胞器之一,主要参与维持胞内钙稳态以及新合成的膜蛋白和分泌型蛋白质的翻译后处理过程。多种病理条件,如缺血、缺氧或中毒等刺激下,诱导细胞发生以伴侣蛋白表达及非折叠蛋白反应启动为特征的内质网应激(ER Stress)。有很多研究报道称ER应激参与了AD的发病过程,但具体机制有待深入研究。内质网分子伴侣(ER molecular chaperones) Bip (Immunoglobulin-binding protein)是内质网中最重要的分子伴侣之一,在内质网应激时表达增高,被认为是内质网应激时最重要的标志之一。Bip在AD病人的大脑皮质和海马中表达明显增高；本课题组以前研究发现持续光照会造成大鼠海马中Bip水平增高,tau蛋白过度磷酸化。Bip与tau过度磷酸化之间的关系及相关机制尚无报道。
糖原合酶激酶-3β(Glycogen synthase kinase-3p, GSK-3p)是在AD发病过程中促使tau蛋白发生过度磷酸化的最重要的磷酸激酶之一,在AD病人脑中GSK-3β过度激活。本课题前期研究发现,ER应激在诱导Bip水平增高、tau蛋白过度磷酸化的同时,激活了GSK-3β;有研究发现,在突变Bip的转基因小鼠中,Bip失去正常功能作用的同时,GSK-3β活性受也到了抑制,上述研究提示Bip和GSK-3β也可能存在着某些必然的联系,但是具体机制不清楚。
因此,本研究利用ER应激诱导剂毒胡萝卜素(Thapsigargin, TG)在整体或细胞水平诱导ER应激,发现GSK-3β激活、tau在Ser396、Ser198/199/202位点发生过度磷酸化；抑制GSK-3β激活,tau磷酸化水平显著降低。进一步利用RNA干扰技术下调Bip水平,TG诱导的tau过度磷酸化显著降低；ER应激及Bip过表达时,Bip可激活GSK-3β、促进GSK-3β与tau特异性结合而诱导tau过度磷酸化。核酸交换因子(Nucleotide exchange factor) Sil1是Bip的重要的共同伴侣分子。本研究发现在ER应激、Bip过表达的细胞中及AD模型小鼠(Tg2576小鼠)脑中Sil1表达明显降低,在细胞水平过表达Sil1通过抑制GSK-3β激活、减少Bip与GSK-3β、tau结合而显著改善TG和Bip过表达诱导的tau过度磷酸化；下调Sil1则Bip水平增高及tau发生过度磷酸化。此外,在培养的大鼠原代海马神经元过表达Bip或下调Sill水平,神经元的轴突生长明显抑制。
本研究系统证明了Bip可通过激活GSK-3β、促进GSK-3β与tau特异性结合而诱导tau过度磷酸化,Sil1对ER应激及Bip过表达诱导的tau蛋白过度磷酸化具有保护作用。研究结果为进一步认识内质网相关的分子伴侣在AD发病中的作用及防治研究提供了依据。
Senile dementia, also named Alzheimer's Disease (AD), the main clinical symptoms of which include cognitive impairment and the degraded learning and memory ability, is characterized by degeneration of neurons. More people may suffer from the risk of AD as the aged society coming, which bring financial burdens to society and families. Senile plaques (SP) and neurofibrillary tangles (NTFs) are the two main pathological changes of AD. NTFs which are compose of hyperphosphorylated tau, are closely positive correlated with the clinical dementia degree of AD patients.
Endoplasmic reticulum (ER) is an important organelle which is involved in the balance of cellular Ca2+, synthesis and modify of proteins after proteins translation. Many pathological stimulation, such as ischemia, hypoxia and poison, induces ER stress, which is characterized as overexpression of ER molecular chaperone and unfolded protein response (UPR). Many researchs demonstrate that ER stress may be contribute to the progress of AD. ER molecular chaperone Immunoglobulin-binding protein (Bip) is important for ER, which increases during ER stress. So Bip is considered as a marker of ER stress. Upregulation of BiP in neurons of temporal cortex and hippocampus of AD patients is found. Our laboratory previously finds hyperphosphorylated tau increases with high-expression Bip in hippocampus of SD rats which suffer from constant illumination. However, the relationship between Bip and tau remains unclear.
Glycogen synthase kinase-3β(GSK-3β) is an important protein phosphorylated kinase of tau. In AD, GSK-3βis activated. Our laboratory previously finds ER stress induces hyperphosphorylation of tau and activation of GSK-3β. And the activity of GSK-3βin knock-out Bip mice is inhibited. So we infer that Bip may be relevant to GSK-3β.
In our research, we induced ER stress in vivo or vitro by inducer thapsigargin (TG). And we found hyperphosphorylation of tau at Ser396, Ser198/199/202 sites and activation of GSK-3β; While TG-induced phosphorylation of tau reduced after knocking down Bip; Overexpression of Bip induced hyperphosphorylation of tau via activating GSK-3βand increasing the association of GSK-3P with tau. Nucleotide exchange factor Sill is the most important nucleotide exchange factor of Bip, disorder of which affect on the energy exchange and fuction of Bip. We found Expression of Sill was reduced in ER stress, Bip-overexpression cells and the brain of Tg2576 mice. Overexpression of Sill reduced TG-induced and Bip-overexpression-induced hyperphophorylation of tau via inhibiting activation of GSK-3P and the binding of Bip with GSK-3βand tau; Knocking down Sill induced overexperssion of Bip and hyperphosphorylation of tau. Furthermore, overexpression of Bip or knocking down Sill remarkably inhibited neuronal axon growth in SD rat primary neurons.
In our study, we demonstrate that Overexpression of Bip induces hyperphosphorylation of tau via activating GSK-3P and increasing the association of GSK-3P with tau; Sill protects from ER stress-induced and Bip-overexpression-induced hyperphosphorylation of tau. In conclusion, our research provides some proofs for the role of ER associative molecular chaperone in progress and prevention of AD.
引文
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