【摘要】：[背景] 卒中是腦損傷的首要原因,缺血性腦卒中是由于腦血流中斷,導(dǎo)致大腦局部缺血的一類嚴(yán)重的神經(jīng)疾病,患者出現(xiàn)語言功能損傷,視力喪失,癱瘓甚至死亡。腦卒中發(fā)病率、死亡率、致殘率居高不下,伴隨著人口老齡化的加劇,腦卒中的發(fā)生率還在逐漸上升,被公認(rèn)為目前嚴(yán)重危害人類健康和生命安全的常見難治性疾病。目前,針對腦缺血造成的損害所采取的治療手段非常有限,目前唯一有效的治療是運(yùn)用組織纖溶酶原激活物(tPA)的溶栓療法。然而,出于安全考慮和溶栓治療的時間窗較窄(4.5小時),多數(shù)患者只能得到對癥支持治療。因此,針對缺血性卒中腦損傷,探討新的干預(yù)方法和治療手段來對抗腦損傷并保護(hù)神經(jīng)細(xì)胞極其重要。 缺血后神經(jīng)元突觸損傷(包括突觸前和突觸后損傷)是引起突觸傳遞障礙與神經(jīng)元死亡的早期病理生理學(xué)基礎(chǔ)。我們課題組前期研究發(fā)現(xiàn)：死亡相關(guān)蛋白激酶(Death Associated Protein Kinase.DAPKl),作為一種Ca2+/鈣調(diào)蛋白依賴的絲氨酸/蘇氨酸激酶,在缺血性腦卒中的缺血腦區(qū)被激活,并介導(dǎo)神經(jīng)元死亡。神經(jīng)元重要的骨架蛋白-微管相關(guān)蛋-Tau,在神經(jīng)元胞體和突起均豐富表達(dá),主要通過促進(jìn)微管組裝以維持軸突轉(zhuǎn)運(yùn)、神經(jīng)元形態(tài)以及神經(jīng)元之間的信號交流。Tau的氨基酸序列中富含絲氨酸/蘇氨酸殘基,許多絲氨酸/蘇氨酸激酶(包括DAPK1)參與神經(jīng)元退行性變性中Tau蛋白異常過度磷酸化,但在缺血性腦損傷過程中,DAPKl是否影響Tau的磷酸化、Tau介導(dǎo)了DAPK1對神經(jīng)元的哪些損傷作用,這些問題至今尚無報(bào)道。Caytaxin作為一種在突觸前豐富表達(dá)的蛋白,能夠調(diào)節(jié)谷氨酸神經(jīng)傳遞,參與神經(jīng)元突觸的凋亡,能引起神經(jīng)退行性改變與神經(jīng)元死亡。激活的DAPK1是否與Caytaxin作用并引起Caytaxin的磷酸化、介導(dǎo)缺血性卒中后突觸前損傷尚不清楚。 [目的] (1)闡明DAPK1與Tau、DAPKl與Caytaxin相互作用介導(dǎo)缺血性卒中后神經(jīng)元死亡的細(xì)胞與分子機(jī)制,為揭示Tau和Caytaxin成為DAPK1下游特異作用底物參與缺血性卒中后神經(jīng)元死亡提供證據(jù),即缺血性卒中后,激活的DAPK1引起Tau蛋白的異常磷酸化并在樹突棘異常聚集,導(dǎo)致樹突棘丟失；而在突觸前激活的DAPK1磷酸化Caytaxin,促進(jìn)Cayatxin的表達(dá),引起突觸傳遞功能障礙。 (2)通過合成小分子多肽阻斷DAPK1與Tau相互作用探討缺血性卒中的治療策略,為研發(fā)缺血性卒中的治療藥物奠定理論基礎(chǔ)。[方法] 運(yùn)用大腦中動脈栓塞(MCAO)手術(shù)以及光照缺血(PT)構(gòu)建4月齡小鼠腦缺血模型或相應(yīng)的Sham假手術(shù)作為對照,分別采用C57BL/6J小鼠、CaMK Ⅱα-Cre小鼠、DAPK1-KDloxp/loxp、DAPK1-KD-/-小鼠為研究對象;CaMK II a-Cre小鼠與DAPK1-KDloxp/loxp小鼠雜交,PCR鑒定陽性小鼠通過他莫西芬誘導(dǎo)得到DAPK1-KD-/-小鼠；通過多普勒腦血流儀和激光散斑腦血管成像儀監(jiān)測MCAO手術(shù)中腦血流的情況;通過磁共振(MRI)和TTC染色檢測小鼠卒中后大腦缺血面積；Fluoro-Jade C (FJ)染色和TUNEL染色鑒定缺血后分別發(fā)生退行性變和凋亡的神經(jīng)元數(shù)目；采用腺相關(guān)病毒(AAV-EGFP)感染標(biāo)記樹突棘；運(yùn)用Western blot(WB)方法檢測缺血后DAPK1、磷酸化肌球蛋白輕鏈(Phospho-myosin light chain, pMLC)、Tau、Caytaxin、剪切型Caspase3(Cleaved-Caspase3),突觸相關(guān)蛋白PSD95、GluR1、Synapsin I等蛋白的表達(dá)水平；通過免疫熒光雙標(biāo)和免疫共沉淀的方法在體內(nèi)和體外研究DAPK1與Tau以及DAPK1與Caytaxin的相互作用情況；在HEK293T細(xì)胞構(gòu)建表達(dá)系統(tǒng),共轉(zhuǎn)DAPK1不同的突變體(DAPK1△KD、DAPK1△CaM、DAPK1△DD、 DAPK1K42A)與Tau,鑒定DAPK1與Tau相互作用的結(jié)構(gòu)域；質(zhì)譜檢測DAPK1免疫沉淀下來的磷酸化蛋白；AAV-Tau-WT以及rAAV-Tau-S262A病毒感染DAPK1-KD+/+原代神經(jīng)元,1AAV-Tau-WT感染DAPK1-KD-/-原代神經(jīng)元,觀察神經(jīng)元樹突棘損傷情況,同時記錄上述神經(jīng)元AMPA受體介導(dǎo)的微型興奮性突觸后電位(mEPSC)的幅度和頻率；合成多肽阻斷DAPK1與Tau的相互作用,靜脈注射TAT-R1D小分子多肽觀察其是否逆轉(zhuǎn)中風(fēng)損傷；運(yùn)用水迷宮、曠場等行為學(xué)手段檢測腦缺血小鼠以及TAT-R1D多肽治療后的小鼠的學(xué)習(xí)記憶和活動情況。 [結(jié)果] 1.腦缺血時樹突棘損傷早于凋亡的發(fā)生 MCAO后再灌注2h到24h,樹突棘密度較假手術(shù)組明顯下降;同時,突觸相關(guān)蛋白PSD95、GluR1和Synapsin I也明顯減少；再灌注6h開始到24h,TUNEL陽性細(xì)胞數(shù)目明顯上升,剪切型的Caspase3再灌注后12h明顯上升。 2.DAPK1通過激酶域與Tau相互作用,DAPK1與Caytaxin在突觸前相互作用 免疫熒光雙標(biāo)和免疫共沉淀的結(jié)果均證實(shí)在缺血缺氧狀態(tài)下DAPK1和Tau以及DAP K1和Caytaxin相互作用形成復(fù)合物,而DAPK1和Tau在缺血后表達(dá)量均未發(fā)生改變,而Caytaxin的表達(dá)水平在缺血側(cè)較對側(cè)有明顯的增加;運(yùn)用GST-pull-down實(shí)驗(yàn)和構(gòu)建細(xì)胞系表達(dá)體系發(fā)現(xiàn)DAPK1通過氨基端的激酶域與Tau特異性結(jié)合；免疫熒光雙標(biāo)顯示DAPK1與Caytaxin在神經(jīng)元中共定位;免疫熒光及免疫印跡均顯示DAPK1與Caytaxin在突觸前表達(dá)；DAPK1與Caytaxin相互作用在缺血性卒中以及神經(jīng)元雙氧水處理后明顯增強(qiáng)。 3.腦缺血時DAPK1被激活,磷酸化Tau Ser262位點(diǎn),磷酸化Caytaxin Ser46位點(diǎn) MCAO后,DAPK1的活性則較假手術(shù)組明顯增加,表現(xiàn)為pMLC的水平明顯增加；GPS21軟件預(yù)測結(jié)果顯示,DAPK1可能磷酸化Tau Ser262位；質(zhì)譜結(jié)果顯示,中風(fēng)后DAPK1磷酸化Tau Ser262位,磷酸化Caytaxin Ser46HEK293T細(xì)胞共轉(zhuǎn)DAPK1和Tau-WT組,Tau pS262以及剪切型的Caspase3水平均明顯升高,而在共轉(zhuǎn)DAPK1和Tau-S262A組則未發(fā)現(xiàn)此現(xiàn)象；C57BL/6J小鼠MCAO2h和24h后Tau pS262水平升高,而pS202, pS422,以及GSK3P水平未觀察到明顯改變。 4.磷酸化Tau Ser262位導(dǎo)致樹突棘損傷 培養(yǎng)9天的原代神經(jīng)元感染rAAV-Tau-WT病毒,12天后觀察出現(xiàn)了樹突棘的丟失,Tau pS262水平上升,突觸相關(guān)蛋白例如PSD95, GluRl和Synapsin I下降,同時AMPA受體介導(dǎo)的微型興奮性突觸后電位(mEPSC)的幅度和頻率均明顯下降,相反的,感染\AV-Tau-S262A以及在DAPK1-KD-/-的原代神元感染Tau-WT未觀察到Tau pS262上調(diào)和上述提及的樹突棘損傷；氧糖剝奪(OGD)處理原代神經(jīng)元60分鐘,感染了Tau-S262A原代神經(jīng)元中TUNEL+/pS262+細(xì)胞數(shù)目明顯少于感染Tau-WT。 5.敲除DAPK1的激酶域減輕缺血損傷 DAPK1-KD-/-小鼠的體重、大腦血管、血流、大腦的結(jié)構(gòu)以及情緒和同窩野生型小鼠相比均未發(fā)生明顯改變,提示條件性敲除DAPK1激酶域沒有影響小鼠的表型;MCAO1h缺血處理,再灌注24小時,磁共振和TTC染色結(jié)果顯示,DAPK1-KD小鼠缺血面積較DAPK1-KDloxp/loxp小鼠明顯下降,Tau pS262水平也明顯下降;再灌注3d和7d后,FJ染色和TUNEL顯示DAPK1-KD-/-小鼠發(fā)生退行性變和凋亡的細(xì)胞減少,同時樹突棘丟失的現(xiàn)象也減輕,而神經(jīng)功能評分以及運(yùn)動運(yùn)動協(xié)調(diào)能力有所改善。 6.TAT-R1D對中風(fēng)損傷產(chǎn)生治療效應(yīng) 根據(jù)DAPK1與Tau相互作用位點(diǎn)合成一段多肽TAT-R1D,熒光顯微鏡觀察腦片,肽段TAT-R1D被神經(jīng)元,而不是被小神經(jīng)膠質(zhì)或者星形膠質(zhì)細(xì)胞吸收；免疫共沉淀結(jié)果顯示靜脈注射TAT-R1D2mg/kg的劑量,再灌注6小時以內(nèi)應(yīng)用TAT-R1D,在腦組織中可以有效的干擾DAPK1-Tau的結(jié)合；MCAO再灌注1小時應(yīng)用TAT-R1D,和應(yīng)用TAT-s-R1D以及生理鹽水比較,Tau pS262下降,突觸相關(guān)蛋白PSD-95、GluR1、Synapsin1較對照組均有所上調(diào)；3d后進(jìn)行TTC染色,缺血面積減少；而且,TAT-R1D顯著地提高TMCAO7天后小鼠的神經(jīng)功能評分和行為學(xué)的表現(xiàn)例如水迷宮和曠場。 [結(jié)論] 我們首次發(fā)現(xiàn)在缺血性卒中小鼠DAPK1與Tau的相互作用介導(dǎo)了卒中后神經(jīng)元樹突棘丟失以及隨后的神經(jīng)元死亡。缺血后激活的DAPK1磷酸化Tau的Ser262位點(diǎn),引發(fā)Tau在樹突棘聚集。利用轉(zhuǎn)基因技術(shù)敲除DAPK1的激酶域或者運(yùn)用小分子多肽TAT-R1D阻斷DAPK1與Tau的相互作用保護(hù)了樹突棘丟失,逆轉(zhuǎn)神經(jīng)功能損傷。而且,我們還初步探討了缺血性卒中DAPK1與Caytaxin的相互作用很可能介導(dǎo)卒中后突觸前功能障礙。因此,針對DAPK1及其下游底物Tau以及Caytaxin的相互作用設(shè)計(jì)小分子多肽進(jìn)行干預(yù),很可能為缺血性卒中的治療提供新的治療靶點(diǎn)與策略。
[Abstract]:[background]
Stroke is the primary cause of brain injury. Ischemic stroke is a serious neurological disease caused by the interruption of cerebral blood flow, resulting in local cerebral ischemia. The patients suffer from language impairment, visual loss, paralysis and even death. The incidence, mortality and disability rate of stroke remain high. With the aging of the population, the incidence of stroke is increasing. The rate is rising and is recognized as a common refractory disease that seriously endangers human health and life safety. Currently, the treatment for cerebral ischemia damage is very limited, and the only effective treatment is thrombolytic therapy with tissue plasminogen activator (tPA). However, safety considerations and thrombolytic therapy are considered. The treatment window is narrow (4.5 hours), and most patients can only get symptomatic support treatment. Therefore, it is very important to explore new intervention methods and treatment methods to combat brain injury and protect nerve cells against ischemic stroke.
Neuronal synaptic damage after ischemia (including presynaptic and postsynaptic damage) is the early pathophysiological basis of synaptic transmission disorders and neuronal death. Our previous study found that death-associated protein kinase (DAPKl) is a Ca2+/calmodulin-dependent serine/threonine. Kinases, which are activated in ischemic brain regions and mediate neuronal death, are abundantly expressed in the somas and processes of neurons, mainly by promoting microtubule assembly to maintain axonal transport, neuronal morphology and signal exchange between neurons. Many serine/threonine kinases (including DAPK1) are involved in abnormal hyperphosphorylation of Tau protein in neurodegenerative disorders. However, whether DAPKl affects Tau phosphorylation during ischemic brain injury and which damage effects of DAPK1 on neurons are mediated by Tau have not been reported so far. As a protein abundantly expressed in presynaptic, n can regulate glutamate transmission, participate in neuronal synaptic apoptosis, and cause neurodegenerative changes and neuronal death. Whether activated DAPK1 acts with Caytaxin and induces Caytaxin phosphorylation, which mediates presynaptic injury after ischemic stroke, remains unclear.
[Objective]
(1) To elucidate the cellular and molecular mechanisms of DAPK1 interacting with Tau, DAPKl and Caytaxin mediating neuronal death after ischemic stroke, and to provide evidence that Tau and Caytaxin are downstream specific substrates of DAPK1 and participate in neuronal death after ischemic stroke. Activated DAPK1 causes abnormal phosphorylation of Tau protein after ischemic stroke Abnormal dendritic spine aggregation leads to the loss of dendritic spine, and the pre-synaptic activation of DAPK1 phosphorylated Caytaxin promotes the expression of Cayatxin, causing synaptic transmission dysfunction.
(2) To explore the therapeutic strategy of ischemic stroke by blocking the interaction between DAPK1 and Tau by synthesizing small molecular polypeptides, so as to lay a theoretical foundation for the development of therapeutic drugs for ischemic stroke.
Middle cerebral artery embolization (MCAO) and light ischemia (PT) were used to construct cerebral ischemia model in 4-month-old mice or sham-operated mice as control. C57BL/6J mice, CaMK II alpha-Cre mice, DAPK1-KD loxp/loxp, DAPK1-KD-/-mice were used as study objects. CaMK II a-Cre mice were hybridized with DAPK1-KD loxp/loxp mice and PCR was used to identify positive. DAPK1-KD-/- mice were induced by tamoxifen; cerebral blood flow during MCAO was monitored by Doppler Cerebral Blood Flowmeter and Laser Speckle Cerebrovascular Imaging; cerebral ischemic area was detected by magnetic resonance (MRI) and TTC staining; degeneration was identified by Fluoro-Jade C (FJ) staining and TUNEL staining, respectively. Number of degenerative and apoptotic neurons; Adeno-associated virus (AAV-EGFP) was used to infect dendritic spines; Western blot (WB) was used to detect DAPK1, Phospho-myosin light chain (pMLC), Tau, Caytaxin, sheared-caspase 3, synapse-related protein PSD95, GluR1, SynapIsin and other eggs after ischemia. The interaction between DAPK1 and Tau, DAPK1 and Caytaxin was studied in vivo and in vitro by immunofluorescence double labeling and immunoprecipitation. The expression system was constructed in HEK293T cells to co-transfect different mutants of DAPK1 (DAPK1 KD, DAPK1 CaM, DAPK1 DD, DAPK1K42A) with Tau, and the interaction between DAPK1 and Tau was identified. Structural domains of DAPK1 immunoprecipitated phosphorylated proteins were detected by mass spectrometry; DAPK1-KD+/+ primary neurons were infected by AAV-Tau-WT and rAAV-Tau-S262A viruses, and DAPK1-KD-/-primary neurons were infected by 1AAV-Tau-WT. The damage of dendritic spines was observed and the AMPA receptor-mediated miniature excitatory postsynaptic potentials (mEPs) were recorded. The amplitude and frequency of EPSC, synthetic peptides blocked the interaction between DAPK1 and Tau, and intravenously injected TAT-R1D small molecule peptides to observe whether they reversed stroke injury. Behavioral methods such as water maze and open field were used to detect the learning, memory and activity of cerebral ischemic mice and those after TAT-R1D polypeptide treatment.
[results]
1. the damage of dendritic spine was earlier than that of apoptosis during cerebral ischemia.
The dendritic spine density decreased significantly from 2 h to 24 h after reperfusion in MCAO group, and the synaptic related proteins PSD95, GluR1 and Synapsin I also decreased significantly. The number of TUNEL positive cells increased significantly from 6 h to 24 h after reperfusion, and the number of shear Caspase 3 increased significantly at 12 h after reperfusion.
2.DAPK1 interacts with Tau through kinase domain, and DAPK1 and Caytaxin interact at presynaptic level.
The results of immunofluorescence double labeling and immunoprecipitation confirmed that DAPK1 and Tau and DAP K1 and Caytaxin interacted to form a complex under hypoxic-ischemic condition, but the expression of DAPK1 and Tau did not change after ischemia, while the expression of Caytaxin increased significantly on the ischemic side compared with the contralateral side. DAPK1 specifically binds to Tau via the amino-terminal kinase domain in the cell line expression system; DAPK1 and Caytaxin co-localize in neurons by immunofluorescence double labeling; both immunofluorescence and immunoblotting show that DAPK1 and Caytaxin are pre-synaptic; interaction between DAPK1 and Caytaxin after ischemic stroke and hydrogen peroxide treatment in neurons Obviously enhanced.
3. DAPK1 was activated during cerebral ischemia, phosphorylation of Tau Ser262 site and phosphorylation of Caytaxin Ser46 site.
After MCAO, the activity of DAPK1 was significantly higher than that of sham-operated group, which showed that the level of pMLC was significantly increased; GPS21 software predicted that DAPK1 might phosphorylate Tau Ser262 site; MS results showed that DAPK1 phosphorylated Tau Ser262 site, phosphorylated Caytaxin Ser46HEK293T cells co-transfected DAPK1 and Tau-WT group, Tau pS262 and shear type. Caspase 3 levels were significantly elevated, but not in DAPK1 and Tau-S262A co-transfected mice; Tau pS262 levels were elevated in C57BL/6J mice after 2 and 24 hours of MCAO, while pS202, pS422, and GSK3P levels were not significantly changed.
4. phosphorylation of Tau Ser262 site results in dendritic spine injury.
After 9 days of culture, primary neurons infected with rAAV-Tau-WT virus showed loss of dendritic spines, elevated levels of Tau pS262, decreased levels of synaptic-related proteins such as PSD95, GluRl and Synapsin I, and decreased amplitudes and frequencies of AMPA receptor-mediated miniature excitatory postsynaptic potentials (mEPSC). On the contrary, AV-Tau-S262A infection resulted in a decrease in the formation of dendritic spines. Tau-WT was infected with DAPK1-KD-/-primitive primordial primordial primordial primordial primordial primordial primordial primordial primordial primordial primordial primordial primordial primordial primordial primordial primordial primordial primordial primordial primordial primordial primordial primordial primordial primordial primordial primordial primordial pri
5. knocking out DAPK1 kinase domain to alleviate ischemic injury
The body weight, cerebral blood vessels, blood flow, brain structure and emotions of DAPK1-KD-/- mice did not change significantly compared with wild-type mice in the same nest, suggesting that conditioned knockout of DAPK1 kinase domain did not affect the phenotype of mice; MCAO1-hour ischemia, reperfusion 24 hours, magnetic resonance imaging and TTC staining showed that the ischemic area of DAPK1-KD mice was larger than that of DAPK1-K mice. In Dloxp/loxp mice, the levels of Tau pS262 and degeneration and apoptosis of DAPK1-KD-/- mice were observed by FJ staining and TUNEL at 3 and 7 days after reperfusion. The loss of dendritic spines was also alleviated, and the neurological function score and motor coordination were improved.
Therapeutic effect of 6.TAT-R1D on stroke injury
A peptide TAT-R1D was synthesized according to the site of interaction between DAPK1 and Tau. Fluorescence microscopy showed that TAT-R1D was absorbed by neurons instead of microglia or astrocytes. Immunocoprecipitation results showed that TAT-R1D could be used in brain tissue at the dose of intravenous TAT-R1D2mg/kg within 6 hours of reperfusion. Tau pS262 decreased, synapse-related proteins PSD-95, GluR1 and Synapsin-1 were up-regulated compared with the control group, TTC staining was performed 3 days later, and the ischemic area was reduced; moreover, TAT-R1D significantly increased the neural function of the mice 7 days after TMCAO. Able to score and behave in behavior such as water maze and open field.
[Conclusion]
We found for the first time that the interaction between DAPK1 and Tau in ischemic stroke mice mediated the loss of dendritic spines and subsequent neuronal death after stroke. The activation of DAPK1 phosphorylated Tau at the site of Ser262 triggered Tau aggregation in the dendritic spines. Blocking the interaction between DAPK1 and Tau protects dendritic spines from loss and reverses neurological impairment. Furthermore, we preliminarily investigated that the interaction between DAPK1 and Caytaxin in ischemic stroke may mediate poststroke presynaptic dysfunction. Row intervention is likely to provide new therapeutic targets and strategies for the treatment of ischemic stroke.
【學(xué)位授予單位】：華中科技大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R743.3

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