本文選題：β-淀粉樣肽 + 腹膜透析　； 參考：《第三軍醫(yī)大學(xué)》2017年博士論文

【摘要】：背景和目的阿爾茨海默病(Alzheimer's disease, AD)是目前老年人中最主要的癡呆類型,是一種以進(jìn)行性的記憶能力下降和認(rèn)知功能障礙為特征的神經(jīng)退行性疾病。AD病因復(fù)雜,迄今為止,其發(fā)病機制尚未闡述清楚。傳統(tǒng)觀點認(rèn)為,AD是大腦自身的疾病。腦內(nèi)β-淀粉樣肽(Amyloid-beta,Aβ)沉積形成的Aβ斑塊(Aβ plaque)是AD最主要的病理特征。目前占主流地位的Aβ級聯(lián)假說認(rèn)為,AD的主要發(fā)生機制是腦內(nèi)Aβ的過度產(chǎn)生或清除障礙導(dǎo)致AP在腦內(nèi)過度沉積,誘發(fā)神經(jīng)炎癥、Tau蛋白過度磷酸化、腦內(nèi)氧化應(yīng)激以及神經(jīng)變性死亡,最終導(dǎo)致癡呆。但是,近年來認(rèn)識到,AD相關(guān)病理不僅局限于大腦。研究發(fā)現(xiàn),Aβ沉積同時存在于腸道、皮膚和心臟,且有可能影響心臟功能。我們和他人的系列研究也表明,如系統(tǒng)慢性感染、心功能不全、肝腎功能不全、慢性肺部感染等系統(tǒng)疾病與Aβ代謝或AD密切相關(guān)。提示系統(tǒng)臟器組織功能狀態(tài)可能參與了 AD的發(fā)生發(fā)展,值得從系統(tǒng)角度來探討AD的發(fā)生機制與防治策略。目前尚無有效預(yù)防或延緩AD進(jìn)展的藥物和方法。Aβ是當(dāng)前AD防治研究的最為重要的靶點,近年來開展了一系列針對Aβ產(chǎn)生和清除的臨床試驗,如Aβ主動與被動免疫治療,β或γ分泌酶抑制劑,但這些試驗都未能取得預(yù)期療效。臨床試驗失敗的重要原因之一是引起嚴(yán)重副作用。在免疫治療臨床試驗中,抗體或藥物進(jìn)入腦內(nèi),在與腦內(nèi)Aβ直接作用同時,導(dǎo)致腦水腫、微出血、無菌性腦膜腦炎以及神經(jīng)元興奮性毒性等副作用。同時,大腦功能的正常運行需要一個高度穩(wěn)定的內(nèi)環(huán)境,外源性藥物通過血腦屏障進(jìn)入腦內(nèi),可改變大腦內(nèi)環(huán)境穩(wěn)態(tài),從而存在誘發(fā)不良反應(yīng)的潛在風(fēng)險。避免藥物進(jìn)入腦內(nèi),通過清除血液Aβ來促進(jìn)腦內(nèi)Aβ外流和清除,可能是更為安全的有效Aβ清除策略。我們過去研究發(fā)現(xiàn),機體外周臟器組織在清除腦內(nèi)Aβ方面具有重要作用,提示增強Aβ外周清除能力有望成為一種安全有效的AD治療策略,值得探討。腹膜透析(peritoneal dialysis, PD)是常被用于清除血液以及腦內(nèi)的有毒物質(zhì),有望成為新的Aβ外周清除措施。為此,本課題擬通過臨床研究和動物實驗來探討腹腔透析清除血液Aβ清除,防治AD的有效性和可行性。這些研究的完成,有助于從系統(tǒng)性角度來理解AD發(fā)生機制,尋找有效防治措施。材料和方法1.收集初次接受腹膜透析的30例慢性腎病(Chronic Kidney Disease, CKD)患者透析前后的血液樣本以及腹膜透析液樣本,檢測并比較三種樣本內(nèi)Aβ水平。2.構(gòu)建小鼠腹膜透析模型。本課題統(tǒng)一使用來自第三軍醫(yī)大學(xué)動物實驗室的雌性C57野生型小鼠(Wt小鼠)為空白對照組,來自美國Jackson實驗室的APPswe/PS 1 dE9(APP/PS 1)轉(zhuǎn)基因小鼠為腹膜透析治療組。實驗組中預(yù)防組設(shè)置為從6月齡開始透析到7月齡終止,治療組設(shè)置為9月齡開始透析到10月齡終止;接受置管手術(shù)但不透析的APP/PS1小鼠為陰性對照組。3.構(gòu)建小鼠腦內(nèi)微透析模型。APP/PS1小鼠和Wt小鼠來源同上。選用9月齡APP/PS1小鼠進(jìn)行微透析實驗,先按上述步驟建立腹膜透析模型。微透析實驗選擇海馬區(qū)進(jìn)行置管,植入微透析探針。手術(shù)10天后,待小鼠傷口愈合,拔出針芯植入半透膜在腹膜透析過程中進(jìn)行微透析實驗。陰性對照為Wt小鼠。4.取材。過量6%水合氯醛麻醉小鼠后打開小鼠胸腔,心尖取血,0.85%的生理鹽水經(jīng)心尖穿刺灌注,剪開右心耳。沿中線切開,取腦稱重。右側(cè)大腦半球于4%多聚甲醛固定,用作免疫染色;左側(cè)大腦半球切取厚度約為100um左右冠狀片子用于Golgi染色,其余部分液氮速凍后,保存于-80℃,用作生化分析。5.AD樣病理改變?nèi)旧?E10、4G8和剛果紅染色檢測Aβ斑塊。6E10、4G8分別與Iba-1共染檢測小膠質(zhì)細(xì)胞吞噬AP的能力。pS396染色檢測Tau磷酸化水平。CD45與GFAP用于檢測膠質(zhì)細(xì)胞增生。6. ELISA檢測。取適量腦組織,TBS勻漿。10級強度超聲,100,000×g4℃離心1小時,取上清液,為可溶性提取物;管底組織繼續(xù)加入200μl 2%SDS液,10級強度超聲,100,000×g 4℃離心1小時,取上清液,為SDS提取物。管底組織繼續(xù)加入200μl 70%FA液,10級強度超聲處理30秒后,100,000×g4℃離心1小時,取上清液,為FA提取物。采用ELISA試劑盒檢測小鼠血液,微透析后液體以及TBS、SDS和FA提取物中的Aβ40和Aβ42水平。腦勻漿中炎癥因子如TNF-α、IFN-γ、IL-1β、IL-6、IL-4和IL-10的水平也用ELISA法檢測。7.免疫印跡。取部分腦組織加入適量RIPA-B裂解液溶解,超聲處理后,于10,00O×g 4℃離心30分鐘。使用BCA法測定樣品總蛋白濃度。配制合適濃度的電泳膠進(jìn)行免疫印跡實驗,本實驗主要使用抗 Aβ、APP-C、sAPP、pS199、pS396、PSD93、PSD95、synapsin-1、synaptophysin、LRP-1和RAGE抗體檢測目標(biāo)蛋白,使用抗Actin抗體作為內(nèi)參。8. Golgi染色。本實驗選用FD Rapid GolgiStain Kit進(jìn)行Golgi染色,實驗方法嚴(yán)格按照試劑盒的說明進(jìn)行。9.行為學(xué)與電生理實驗。預(yù)防組與治療組APP/PS1小鼠都進(jìn)行Y-迷宮與曠場實驗,治療組動物進(jìn)一步通過電生理實驗檢測腹膜透析對APP/PS1小鼠海馬區(qū)長時程增強(Long-term Potentiation,LTP)的影響。結(jié)果1.腹膜透析降低CKD病人以及APP/PS1小鼠血液中Aβ水平。2.微透析實驗表明,腹膜透析在降低小鼠血液中Aβ的同時可以迅速降低小鼠腦內(nèi)ISF中的Aβ水平,并且小鼠血液與ISF中的Aβ變化趨勢相關(guān)。3.在預(yù)防實驗和治療實驗中,腹膜透析均能降低APP/PS1小鼠腦內(nèi)Aβ水平。4.腹膜透析小鼠腦內(nèi)TNF-α、IFN-γ和IL-6水平均明顯降低IL-10水平顯著升高,且其腦內(nèi)異�；罨男∧z質(zhì)細(xì)胞和星形膠質(zhì)細(xì)胞顯著減少。5.腹腔透析提高腦內(nèi)小膠質(zhì)細(xì)胞對Aβ的吞噬能力有。6.腹膜透析改善APP/PS1小鼠腦內(nèi)AD相關(guān)病理:海馬神經(jīng)元死亡減少,tau蛋白磷酸化水平(pS199和pS396)降低,軸突密度增加,神經(jīng)元突觸棘數(shù)量增加。7.腹膜透析改善APP/PS1小鼠認(rèn)知功能:治療組小鼠行為學(xué)結(jié)果,包括Y-迷宮(自發(fā)交替反應(yīng)與新臂識別實驗)和曠場實驗檢測結(jié)果得到顯著改善。電生理實驗提示腹膜透析顯著改善APP/PS1小鼠海馬區(qū)LTP。討論本研究中,我們發(fā)現(xiàn)腹膜透析可有效降低血液與ISF中的可溶性Aβ水平。在為期一個月的透析后,APP/PS1小鼠腦內(nèi)的Aβ負(fù)荷、神經(jīng)炎癥、神經(jīng)退行性變以及認(rèn)知功能均有所改善。其可能機制是腹膜透析可以減少血液中的Aβ,從而促進(jìn)腦內(nèi)的Aβ外流,改善腦內(nèi)炎癥微環(huán)境并增強小膠質(zhì)細(xì)胞Aβ吞噬能力。外周清除最重要的基礎(chǔ)是Aβ可以穿過血腦屏障(Blood Brain Barrier,BBB)。傳統(tǒng)觀點認(rèn)為AD患者BBB轉(zhuǎn)運功能受損,會減少腦內(nèi)Aβ流出,促進(jìn)外周Aβ內(nèi)流。近期研究卻提示AD病人以及APP/PS1小鼠的BBB功能相對完整。本研究中,我們首次探討了血液Aβ的減少與腦內(nèi)ISF中Aβ減少之間的動力學(xué)關(guān)系,研究結(jié)果支持APP/PS1小鼠BBB轉(zhuǎn)運功能的完整性,也為外周途徑清除腦內(nèi)Aβ提供理論依據(jù)。我們進(jìn)一步探討了腹膜透析模型減少APP/PS1小鼠腦內(nèi)Aβ的具體機制。通過計算,我們發(fā)現(xiàn)在治療組中為期一個月腹膜透析直接清除的Aβ總量約為7.2ng。而10月齡的APP/PS1小鼠腦內(nèi)的Aβ濃度約為1ng/mg,其大腦質(zhì)量約為360mg,故可以計算出10月齡APP/PS1小鼠腦內(nèi)AP總量約360ng。治療組接受腹膜透析的APP/PS1小鼠腦內(nèi)減少的Aβ為腦內(nèi)AP總量的20.44%(約72ng)。因此,通過腹膜透析液直接清除的Aβ只占總Aβ減少量的10%,這提示在腹膜透析時還有其他的途徑參與Aβ清除。通過免疫印跡實驗發(fā)現(xiàn)在接受腹膜透析的APP/PS1小鼠LRP-1表達(dá)增加而RAGE表達(dá)減少,提示腦內(nèi)Aβ向外周轉(zhuǎn)運增強。另外,腹膜透析后其小膠質(zhì)細(xì)胞Aβ吞噬的能力增強,促進(jìn)了 Aβ的清除。此外,腹膜透析小鼠大網(wǎng)膜內(nèi)Aβ沉積量明顯高于對照組,提示大網(wǎng)膜也可能吸附部分Aβ。這些結(jié)果提示腹腔透析通過多種途徑來實現(xiàn)對腦內(nèi)Aβ的清除。當(dāng)然,CKD患者與APP/PS1小鼠之間存在很多差異。課題組前期的工作已證實在CDK患者群體中,其血液中的Aβ水平顯著高于正常對照組。這表明對腎臟功能受損的CDK患者而言,其外周Aβ清除功能也同樣受損。而APP/PS1小鼠的腎功能雖然正常,但并不足以清除由于腦內(nèi)Aβ過度產(chǎn)生引起的血液中急劇升高的Aβ。因此,CDK患者與APP/PS1小鼠之間都存在清除能力與Aβ水平之間不匹配的矛盾。因此,即使外周臟器功能沒有受損,增強血液中Aβ清除能力也是AD防治的有效方法。另一個差異是,臨床上CKD病人常用的透析方案為持續(xù)不臥床腹膜透析,全天都在進(jìn)行透析。而本研究動物實驗中APP/PS1小鼠每天僅接受兩個小時的透析。這種短時間的透析便可以有效清除APP/PS1小鼠腦內(nèi)Aβ,提示對AD患者而言,持續(xù)不臥床腹膜透析可能會取得更好的效果。而且,過去的尸檢研究也支持透析療法可以清除人體腦內(nèi)的Aβ沉積。本研究為通過外周途徑來清除腦內(nèi)Aβ、恢復(fù)大腦內(nèi)環(huán)境提供了概念驗證性證據(jù);也為通過外周途徑來防治帕金森病、亨廷頓綜合征以及肌萎縮側(cè)索硬化等蛋白異常折疊的神經(jīng)退行性疾病提供了新思路。結(jié)論腹腔透析能夠通過清除血液Aβ、改善血腦屏障Aβ轉(zhuǎn)運功能、增強腦內(nèi)小膠質(zhì)細(xì)胞Aβ吞噬能力等途徑,清除腦內(nèi)Aβ沉積、減輕AD相關(guān)病理、改善APP/PS1小鼠認(rèn)知功能,提示腹腔透析是AD防治的潛在方法。
[Abstract]:Background and objective Alzheimer's disease (AD) is the most important type of dementia in the elderly. It is a neurodegenerative disease characterized by progressive memory impairment and cognitive dysfunction. The pathogenesis of.AD is complex. So far, the pathogenesis of the disease is not yet clear. The traditional view is that AD is the brain itself. The A beta plaques (A beta plaque) deposited by Amyloid-beta (A beta) in the brain are the most important pathological features of AD. The dominant mechanism of A beta cascade in the mainstream is that the main mechanism of AD is the excessive production or removal of A beta in the brain resulting in excessive deposition of AP in the brain, induced neuroinflammation, and excessive phosphorylation of Tau protein. It has been recognized in recent years that AD related pathology is not only limited to the brain. Research has found that A beta deposition is also found in the intestines, skin and heart, and may affect cardiac function. Our and other series of studies have also shown that chronic infection of the system, heart dysfunction, liver Systemic diseases such as renal insufficiency and chronic pulmonary infection are closely related to A beta metabolism or AD. It is suggested that the functional state of systemic organs may be involved in the development of AD. It is worth to discuss the pathogenesis and prevention strategy of AD from a systematic point of view. At present, there is no drug and method of.A beta to prevent or delay the development of AD, which is the current study on the prevention and control of AD. The most important target is a series of clinical trials on A beta production and removal in recent years, such as A beta active and passive immunotherapy, beta or gamma secretase inhibitors, but these tests have failed to achieve the expected effect. One of the important reasons for the failure of clinical trials is the severe side effects. In the clinical trials of immunotherapy, antibodies or As the drug enters the brain, it leads to the side effects of brain edema, micro bleeding, aseptic meningoencephalitis, and excitotoxicity of neurons, as well as the direct action of A beta in the brain. At the same time, the normal functioning of the brain needs a highly stable internal environment, and exogenous drugs enter the brain through the blood brain barrier, which can change the homeostasis of the brain. The potential risk of inducing adverse reactions. Avoiding drugs entering the brain and promoting A beta Exodus and scavenging through the removal of A beta in the brain may be a safer and more effective A beta clearance strategy. As a safe and effective AD treatment strategy, it is worthwhile to explore. Peritoneal dialysis (PD) is often used to remove blood and toxic substances in the brain. It is expected to be a new A beta peripheral clearance measure. Therefore, this subject is intended to explore the effectiveness of clearing blood A beta clearance in peritoneal dialysis by clinical and animal experiments. The effective prevention and treatment of AD is effective. The completion of these studies helps to understand the AD mechanism from a systematic perspective and to find effective preventive measures. Material and methods 1. collect blood samples from 30 patients with chronic renal disease (Kidney Disease, CKD) and Liquor Dialysisintraperitoneus samples for the first time of peritoneal dialysis, and to compare and compare three samples. The mouse peritoneal dialysis model was constructed with the internal A beta level.2.. The female C57 wild type mice (Wt mice) from the animal laboratory of Third Military Medical University were used as the blank control group. The APPswe/PS 1 dE9 (APP/PS 1) transgenic mice from the Jackson Laboratory of the United States were used as the peritoneal dialysis treatment group. The prevention group in the experimental group was set from 6 month old. From the beginning of dialysis to 7 month old termination, the treatment group was set to start from 9 month old to 10 month old to terminate, and the APP/PS1 mice who received catheterization but without dialysis were negative control group.3.. The microdialysis model.APP/PS1 mice and the Wt mice were the same as the same. 9 month old APP/PS1 mice were selected for microdialysis, and the above steps were set up to establish the abdomen. A microdialysis model was used in the microdialysis experiment. The microdialysis probe was implanted in the hippocampus and the microdialysis probe was implanted in the hippocampus. After 10 days, the wound healed and the needle core was inserted into the microdialysis process during the peritoneal dialysis. The negative control was taken from the.4. of Wt mice. After the excess of 6% chloral aldehyde intoxicated mice, the mice were opened to the thoracic cavity, the apical blood was taken, 0.85% of the blood. The normal saline was perfused through the apical puncture and cut open the right auricle. The brain was cut along the middle line to weigh the brain. The right hemisphere was fixed with 4% polyformaldehyde and used as immune staining. The left cerebral hemisphere was cut to about 100um and about Golgi staining. The rest of the liquid nitrogen was frozen at -80 C, used for biochemical analysis of.5.AD like pathological changes. .6E10,4G8 and Congo red staining were used to detect the ability of A beta plaque.6E10,4G8 to detect the phagocytosis of AP in microglia and.PS396 staining,.PS396 staining was used to detect Tau phosphorylation level.CD45 and GFAP for.6. ELISA detection of glial cell proliferation. Appropriate amount of brain tissue, TBS homogenate level intensity hyperacoustic, 100000 x centrifuge 1 hours, supernatant, For the soluble extract, the tube bottom tissue continued to add 200 mu L 2%SDS liquid, 10 grade intensity ultrasound, 100000 x g 4 C centrifuge for 1 hours, and take the supernatant for SDS extract. The tube bottom tissue continued to add 200 mu L 70%FA solution, 10 grade intensity ultrasonic treatment for 30 seconds, 100000 x G4 centigrade centrifuge 1 hours, and the supernatant was FA extract. ELISA kit was used to detect mice. Blood, after microdialysis, and the levels of A beta 40 and A beta 42 in the extracts of TBS, SDS and FA. The levels of inflammatory factors such as TNF- alpha, IFN- gamma, IL-1 beta, IL-6, IL-4 and IL-10 were also detected by ELISA method. The method was used to determine the total protein concentration of the sample. A suitable concentration of gel electrophoresis was used to carry out the immunoblotting experiment. The experiment mainly used anti A beta, APP-C, sAPP, pS199, pS396, PSD93, PSD95, synapsin-1, synaptophysin, LRP-1 and RAGE antibody detection target protein. Golgi staining was carried out, and the experimental methods were carried out strictly according to the instructions of the kit for.9. behavior and electrophysiological experiments. The prevention group and the APP/PS1 mice in the treatment group were all carried out by the Y- maze and the open field experiment. The treatment group was further examined by electrophysiological tests to detect the long history enhancement (Long-term Potentiation, LTP) in the hippocampus of APP/PS1 mice by peritoneal dialysis. Results 1. peritoneal dialysis reduced CKD patients and APP/PS1 mice blood A beta level.2. microdialysis experiment showed that peritoneal dialysis could reduce the A beta level of ISF in the brain of mice rapidly while reducing the A beta in the blood of mice, and the.3. in the mice blood and the A beta in ISF, in the preventive experiment and the treatment experiment, peritoneum permeation. The average level of A beta in the brain of APP/PS1 mice decreased the TNF- alpha in the brain of.4. peritoneal dialysis mice, IFN- gamma and IL-6 water decreased significantly, and the abnormal activation of microglia and astrocytes in the brain significantly decreased.5. peritoneal dialysis and increased the phagocytosis of microglia to A beta in the brain, and.6. peritoneal dialysis improved AP. P/PS1 mouse brain AD related pathology: hippocampal neuronal death decreased, tau protein phosphorylation level (pS199 and pS396) decreased, axon density increased, neuronal synapse spines increased.7. peritoneal dialysis to improve the cognitive function of APP/PS1 mice: the behavioral results of the treatment group, including the Y- maze (spontaneous alternating reaction and new arm recognition experiment) and the open field The experimental results have been significantly improved. Electrophysiological experiments suggest that peritoneal dialysis significantly improves the LTP. discussion in the hippocampus of APP/PS1 mice. We found that peritoneal dialysis can effectively reduce the levels of soluble A beta in the blood and ISF. After one month's dialysis, the A beta load, neuroinflammation, and neurodegenerative changes in the brain of APP/PS1 mice. The possible mechanism is that peritoneal dialysis can reduce the A beta in the blood, thus promote A beta Exodus in the brain, improve the microenvironment in the brain and enhance the phagocytosis of microglia A beta. The most important basis for peripheral clearance is that A beta can pass through the blood brain barrier (Blood Brain Barrier, BBB). The impaired BBB transport function can reduce the A beta outflow in the brain and promote the peripheral A beta flow. Recent studies have suggested that the BBB function of the AD patients and the APP/PS1 mice is relatively complete. In this study, we first explored the kinetic relationship between the decrease of A beta in the blood and the A beta reduction in the ISF in the brain. The results support the completion of BBB transport function of APP/PS1 mice. Integrality also provides a theoretical basis for the removal of A beta in the brain by peripheral pathways. We further explored the specific mechanism of A beta in the brain of APP/PS1 mice by peritoneal dialysis model. By calculation, we found that the total amount of A beta directly removed by peritoneal dialysis for one month in the treatment group was about 7.2ng. and the concentration of A beta in the brain of 10 month old APP/PS1 mice was approximately equal to that of the APP/PS1 mice. 1ng/mg, with a brain mass of about 360mg, can be calculated in the brain of 10 month old APP/PS1 mice that the total amount of AP in the brain of the 360ng. treatment group is 20.44% (about 72ng) in the brain AP in the APP/PS1 mice receiving peritoneal dialysis. Therefore, the A beta, which is directly removed by Liquor Dialysisintraperitoneus, is only 10% of the total A beta reduction, which suggests that in peritoneal dialysis. There were other ways to participate in A beta clearance. Through immunoblotting, the expression of LRP-1 in the APP/PS1 mice received peritoneal dialysis was increased and the expression of RAGE decreased, suggesting the enhancement of A beta transshipment in the brain. In addition, the ability of A beta phagocytosis in the microglia was enhanced after peritoneal dialysis, and the clearance of A beta was promoted. In addition, peritoneal dialysis mice omentum was also found. The amount of internal A beta was significantly higher than that of the control group, suggesting that the greater omentum may also adsorb partial A beta. These results suggest that peritoneal dialysis can achieve the clearance of A beta in the brain through a variety of pathways. Of course, there are many differences between the CKD patients and the APP/PS1 mice. The earlier work of the group has proved that the level of A beta in the blood is significant in the group of CDK patients. It was higher than the normal control group. This showed that the peripheral A beta scavenging function was also impaired in CDK patients with impaired renal function. While the renal function of APP/PS1 mice was normal, it was not sufficient to clear the A beta caused by the excessive production of A beta in the brain. Therefore, there was a clear clearance between CDK patients and APP/PS1 mice. A beta levels are inconsistent. Therefore, even if the peripheral viscera function is not damaged, the enhancement of A beta clearance in the blood is also an effective method for the prevention and treatment of AD. The other difference is that the commonly used dialysis scheme for the clinical CKD patients is continuous ambulatory peritoneal dialysis and is dialytic all day. In this study, the APP/PS1 mice were tested every day in this study. Only two hours of dialysis. This short time dialysis can effectively remove A beta in the brain of APP/PS1 mice, suggesting that continuous ambulatory peritoneal dialysis for AD patients may achieve better results. Moreover, past autopsy studies also support the removal of A beta in the brain of the human body. This study is through the peripheral pathway. It provides a conceptual proof for the removal of A beta in the brain and the restoration of the internal environment of the brain. It also provides new ideas for the prevention and treatment of abnormal foldable neurodegenerative diseases such as Parkinson's disease, Huntington's syndrome and amyotrophic lateral sclerosis. Conclusion peritoneal dialysis can improve the A beta transport of the blood brain barrier by removing the blood A beta. Function, enhancing the phagocytosis of A beta in brain microglia, clearing the A beta in the brain, alleviated AD related pathology and improving the cognitive function of APP/PS1 mice, suggesting that peritoneal dialysis is a potential method for the prevention and treatment of AD.

【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R749.16

【參考文獻(xiàn)】

相關(guān)期刊論文 前1條

1 肖愛武;何敬;王茜;羅藝;孫燕;周艷平;官陽;Paul J.Lucassen;戴甲培;;阿爾茨海默病老年斑及磷酸化tau蛋白的形成和發(fā)展與軸突病變相關(guān)(英文)[J];Neuroscience Bulletin;2011年05期

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