王國佐　龔盛強　尹　芳　王珊珊　易壓喬　成紹武

(1 湖南中醫(yī)藥大學中西醫(yī)結(jié)合學院,長沙,410208; 2 湖南中醫(yī)藥大學中醫(yī)學院,長沙,410208)

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腦血管疾病與阿爾茨海默病的聯(lián)系及其機制

王國佐1龔盛強1尹芳1王珊珊1易壓喬2成紹武1

(1 湖南中醫(yī)藥大學中西醫(yī)結(jié)合學院,長沙,410208; 2 湖南中醫(yī)藥大學中醫(yī)學院,長沙,410208)

腦血管疾病和阿爾茨海默病(AD)之間存在很大程度的交叉重疊(如共同的危險因素和某些相同的病理變化),提示它們可能在影響認知功能下降方面具有相加或協(xié)同作用。腦老化和AD最常見的血管病變是腦淀粉樣血管病變和小血管病變,高達84%的老年AD患者顯示不同程度的腦血管疾病的病理改變。雖然目前不能確定腦血管病變是影響AD的發(fā)生還是發(fā)展,但是它確實在AD的神經(jīng)元功能紊亂中起重要作用。進一步闡明腦血管疾病和AD影響認知功能下降的機制對于全面理解AD神經(jīng)退變的發(fā)生和發(fā)展有著重要的意義,將為AD的預防和治療提供新的思路。

阿爾茨海默病；腦血管疾??；腦淀粉樣血管??；認知損害

長期以來,腦血管疾病(Cerebrovascular Disease,CVD)與阿爾茨海默病(Alzheimer′s Disease,AD)之間的聯(lián)系是大家所關(guān)注的話題。隨著年齡的增長,AD和腦血管病的發(fā)病率均增加,能引起腦血管病的危險因素也同樣能促發(fā)AD,除了衰老這一重要因素外,高血壓、吸煙、高血脂、糖尿病、同型半胱氨酸、ApoE4基因亞型、動脈粥樣硬化等都是它們共同的危險因素[1-2]。最近研究顯示,腦血管疾病在AD的發(fā)病機制中發(fā)揮重要的作用,有的研究者甚至認為AD是一種腦血管性疾病而不是神經(jīng)退行性疾病[3-5]。

1　腦血管疾病在衰老過程中常見類型及對AD的影響

衰老使AD和腦血管疾病的發(fā)病率均增加。最近研究顯示,老年人中腦血管病明顯增加了AD發(fā)生的危險性,尤其是在疾病的早期可進一步強化阿爾茨海默病樣病理改變的作用,進而促進癡呆的發(fā)生并使其程度加重[6]。特別是在AD的初期階段,腦血管病變可影響和加重認知功能障礙,降低臨床癡呆發(fā)生的閾值[7-8]。

老年人腦血管病變的類型主要包括:腦淀粉樣血管病(CAA),腦動脈粥樣硬化,小血管疾病(在大多數(shù)情況下由高血壓引起,即高血壓血管病變),或微血管退變(迂曲、纖維化和脂質(zhì)透明變性),血腦屏障(BBB)功能障礙引起的腦白質(zhì)病變(WMLs),微型腦梗死,腔隙或腔隙性梗死,顱內(nèi)微型出血等等。所有這些病癥可能會破壞腦血管的完整性,并改變腦灌注導致神經(jīng)元損傷和認知功能障礙。有大量數(shù)據(jù)支持AD患者腦內(nèi)存在不同程度的腦血管病變,如Kalaria和Ballard[9]通過300例AD患者的尸檢結(jié)果表明,98%患者腦內(nèi)有腦淀粉樣血管病變(Cerebral Amyloid Angiopathy,CAA),100%存在不同程度的微血管退行性病變,31%有不同程度的腦梗死和7%患者有顱內(nèi)出血。而Olichney[10]在248例AD患者的尸檢結(jié)果也顯示,48%有腦血管損傷,31%患者伴有微型腦梗死,12.5%患者有大型腦梗死和13.5%有顱內(nèi)出血。通過比較173例AD患者和130例正常老年人結(jié)果顯示,腦血管損傷在AD患者所占比率(56.4%)明顯比正常對照高(42.4%)[11]。這些研究表明,腦血管病在AD的發(fā)生和發(fā)展方面起著很大的作用。最近通過對來源于國際阿爾茨海默病協(xié)調(diào)中心(National Alzheimer′s Coordinating Center,NACC)數(shù)據(jù)庫的5715例患者評估,確認了腦血管病變在AD患者中的發(fā)病率,揭示它們可能在影響認知功能下降方面具有相加或協(xié)同作用[12-14]。然而,它們影響認知功能的結(jié)合作用具體機制尚不明確,而且在流行病學和臨床病理研究得出的結(jié)果顯示它們之間的相互關(guān)系尚存爭議[15-19]。

2　腦血管疾病影響阿爾茨海默病的機制

傳統(tǒng)理論認為腦血管病變僅與血管性癡呆(Vascular Dementia,VD)相關(guān),上面的AD與腦血管病關(guān)系的證據(jù)說明腦血管病在AD的發(fā)生和發(fā)展方面起著很大的作用,其聯(lián)系機制可能有以下幾點:

2.1腦組織血流灌注障礙大量研究表明,慢性腦組織低灌注可導致區(qū)域性突觸前和突觸后改變、蛋白合成異常及能量代謝調(diào)節(jié)障礙、葡萄糖利用減少、膽堿能受體喪失,也可促發(fā)海馬區(qū)微血管病變及其輻射神經(jīng)元損傷[20]。區(qū)域性低灌注在散發(fā)性及家族性AD中均為較早期的發(fā)現(xiàn),AD患者的局部腦血流確有明顯下降。另外,目前改善AD認知水平的治療藥物如膽堿酯酶抑制劑也能通過增加腦灌注改善病情[21-22]。

腦血管疾病已被證明能誘導β淀粉樣蛋白(Aβ)的沉積,小血管病變導致血腦屏障結(jié)構(gòu)和功能上的破壞,引起ApoE蛋白從腦內(nèi)泄漏和Aβ在腦血管周圍的星型膠質(zhì)細胞聚集[23],導致Aβ的沉積[24]。這種沉積也會造成腦內(nèi)微血管退行性病變,導致腦血流灌注障礙。而且腦血管疾病也會造成血腦屏障破壞和腦內(nèi)淀粉樣蛋白主要成分Aβ的代謝障礙,加重血管壁淀粉樣沉積,進一步加重血管腔的狹窄和供血障礙,形成惡性循環(huán)[25]。慢性腦組織低灌注可以通過影響腦內(nèi)能量代謝,減低三磷酸腺苷(ATP)合成和產(chǎn)生氧自由基,引起神經(jīng)元損傷而加重神經(jīng)元缺失。ATP合成降低會激活相關(guān)蛋白激酶,導致tau蛋白異常磷酸化,并使tau蛋白的翻譯后修飾過程異常[26]。

2.2血管新生異常在AD患者腦中存在血管新生異常,表現(xiàn)為毛細血管密度減小和腦內(nèi)皮細胞壁退化。Bell等報道AD患者6個腦區(qū)域的毛細血管密度比正常對照組少17%左右,其中在距狀裂皮質(zhì)區(qū)域減少18%[27]。Bailey等[28]研究表明,腦內(nèi)毛細血管密度的降低與AD患者臨床癡呆程度相關(guān)。但也有研究表明,AD腦內(nèi)某些局部區(qū)域毛細血管密度增高[29]。

腦內(nèi)血管新生是在已有血管的基礎(chǔ)上通過刺激內(nèi)皮細胞的增殖、遷移和骨髓衍生細胞異質(zhì)群(包括EPCs、周祖細胞等)的募集。EPCs摻入脈管系統(tǒng)分化為內(nèi)皮細胞,而PPCs發(fā)育成熟為周細胞和血管平滑肌細胞。正常情況下,腦內(nèi)缺氧會調(diào)節(jié)缺氧誘導因子-1(HIF-1)的表達誘導血管的新生,該過程主要通過血管內(nèi)皮生長因子(VEGF)來實現(xiàn);而當VEGF不足時,血管細胞凋亡[30]。有研究指出,AD患者大腦血管密度異?？赡芘cAβ的聚集有關(guān),雖然在AD患者VEGF水平增高,但Aβ與VEGF因子結(jié)合沉積在淀粉樣斑塊中,從而導致AD病理過程中的神經(jīng)退行性病變以及抑制血管新生[31]。在AD發(fā)病早期,VEGF表達增加可對抗血管缺乏和低灌注。但隨著AD的發(fā)展,VEGF不斷在Aβ斑塊周圍沉積,VEGF與Aβ斑塊緊密結(jié)合,最終導致局部VEGF缺乏,損傷其神經(jīng)保護功能即血管再生。異常血管生成或內(nèi)皮老化引起Aβ清除受體(LRP)水平降低或流入受體RAGE水平增加將導致Aβ在血腦屏障不完全清除[32]。同時,缺氧引起血管生成素-2(Ang-2)水平升高,占領(lǐng)Tie-2受體,阻止血管生成素-1(Ang-1)與它結(jié)合,導致毛細血管周細胞游離出來,影響毛細血管的穩(wěn)定性,破壞血腦屏障[33]。

2.3炎性反應異常越來越多的實驗和臨床證據(jù)表明,在AD的發(fā)生發(fā)展過程中,始終伴隨著慢性炎性反應,多種膠質(zhì)細胞及炎性反應因子參與其中的炎性反應損傷病理過程。腦血管疾病中,損傷的腦血管壁細胞(特別是血管內(nèi)皮細胞)激發(fā)炎性反應,釋放大量炎性反應因子損傷神經(jīng)細胞。AD腦內(nèi)微血管釋放大量的促炎因子,如一氧化氮(NO)、凝血酶(thrombin)、腫瘤壞死因子a(TNF-a)、轉(zhuǎn)化生長因子β(TGF-β)、白介素1β(IL-1β)、IL-6、IL-8和基質(zhì)金屬蛋白酶(MMPs)等[34],這些炎性反應因子水平比正常人腦血管內(nèi)含量明顯升高。體外實驗結(jié)果也表明,AD患者來源的微血管與神經(jīng)元共培養(yǎng)出現(xiàn)明顯的神經(jīng)毒性,而與正常微血管培養(yǎng)表現(xiàn)的神經(jīng)毒性明顯減少或無毒性[35]。這種神經(jīng)毒性可能與腦血管內(nèi)皮細胞功能障礙有關(guān),有研究表明,應用促炎因子IL-1β和LPS刺激腦血管內(nèi)皮細胞釋放的因子能殺死膽堿能神經(jīng)元[36]。

而且炎性反應和氧化應急損傷腦內(nèi)皮細胞還能誘導產(chǎn)生神經(jīng)毒性蛋白酶-凝血酶(thrombin)。在AD腦內(nèi)thrombin及其受體PAR-1水平顯著升高,它是老年斑淀粉樣沉淀的成份[37]。thrombin能通過直接和間接的途徑對神經(jīng)元產(chǎn)生毒性作用,研究表明它能刺激小膠質(zhì)細胞的JAK2-STAT3信號通路增加TNF-a和誘導型NO表達[38],還能通過調(diào)節(jié)星型膠質(zhì)細胞ERK1/2信號通路增加MMP-9表達[39]。它還通過影響神經(jīng)元細胞周期、促凋亡和NADPH氧化酶介導的氧化應激等發(fā)揮直接神經(jīng)毒性,腦室內(nèi)直接給予thrombin導致神經(jīng)細胞死亡和認知功能障礙[40]。同時,研究發(fā)現(xiàn)蛋白酶nexin-1(thrombin抑制劑)活性在AD腦內(nèi),特別是腦血管周圍顯著減少,說明thrombin主要從血管釋放[41]。

3　結(jié)論

傳統(tǒng)觀點認為,AD疾病進程的起始因素是神經(jīng)元退變,神經(jīng)血管病理變化是神經(jīng)元損傷后的繼發(fā)事件。然而,單純的神經(jīng)元功能紊亂僅能影響神經(jīng)活動引起腦血流灌注的變化,并不能引起中樞動脈粥樣硬化,軟膜和腦內(nèi)動脈血管生成,血管老化和微血管病理改變,不能引發(fā)腦血管炎性反應、BBB轉(zhuǎn)運體缺陷或者發(fā)生在AD的血管修復。雖然目前不能確定腦血管病變是影響AD的發(fā)生還是發(fā)展,但是它確實在AD的神經(jīng)元功能紊亂中起重要作用。它們之間的聯(lián)系機制的闡明對于全面理解AD神經(jīng)退變的發(fā)生和發(fā)展有著重要的意義,將為AD的預防和治療提供新的思路。

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(2016-04-10收稿責任編輯：王明)

Connection and Mechanism Between Cerebrovascular Disease and Alzheimer′s Disease

Wang Guozuo1, Gong Shengqiang1,Yin Fang1,Wang Shanshan1,Yi Yaqiao2，Cheng Shaowu1

(Department of integrated Chinese and Western medicine, Hunan University of Chinese Medicine, Hunan KeyLaboratoryofIntegratedChineseandWesternMedicine,Changsha410208,China)

Epidemiological and clinico-pathological data indicate that there is considerable overlap between Cerebrovascular disease (CVD) and Alzheimer′s disease (AD) and suggest that there are additive or synergistic effects of both pathologies on cognitive decline. The most frequent vascular pathologies in the aging brain and in AD are cerebral amyloid angiopathy and small vessel disease. Up to 84% of aged subjects show morphological substrates of CVD in addition to AD pathology. Although the effects of CVD on the development and progression of dementia are unclear, it has been well confirmed that CVD contributes to the neurodegeneration of AD. Further study of the relationship between CVD and AD will allow us to fully understand the mechanism of the development and progression of dementia and lead to the discovery of other novel therapeutic targets for AD.

Alzheimer′s disease; Cerebrovascular disease; Cerebral amyloid angiopathy; Cognitive impairment

國家自然科學基金青年項目(編號: 81202794)——“特異性蛋白質(zhì)相互作用網(wǎng)絡(luò)在腦梗死發(fā)生中的作用及中藥腦泰方干預機制研究”

王國佐(1978.08—)，男，在讀博士研究生，副教授，研究方向：中西醫(yī)結(jié)合防治心腦血管疾病研究，E-mail:1586074663@qq.com

成紹武(1976.02—)，男，博士后，教授，湖南中醫(yī)藥大學中西醫(yī)結(jié)合防治心腦血管疾病湖南省重點實驗室副主任，研究方向:衰老神經(jīng)生物學與中藥抗衰老，E-mail:docshwcheng@hotmail.com

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A doi：10.3969/j.issn.1673-7202.2016.09.066