脑血管疾病与阿尔茨海默病的联系及其机制

王国佐　龚盛强　尹　芳　王珊珊　易压乔　成绍武

(1 湖南中医药大学中西医结合学院,长沙,410208; 2 湖南中医药大学中医学院,长沙,410208)



脑血管疾病与阿尔茨海默病的联系及其机制

王国佐1龚盛强1尹芳1王珊珊1易压乔2成绍武1

(1 湖南中医药大学中西医结合学院,长沙,410208; 2 湖南中医药大学中医学院,长沙,410208)

脑血管疾病和阿尔茨海默病(AD)之间存在很大程度的交叉重叠(如共同的危险因素和某些相同的病理变化),提示它们可能在影响认知功能下降方面具有相加或协同作用。脑老化和AD最常见的血管病变是脑淀粉样血管病变和小血管病变,高达84%的老年AD患者显示不同程度的脑血管疾病的病理改变。虽然目前不能确定脑血管病变是影响AD的发生还是发展,但是它确实在AD的神经元功能紊乱中起重要作用。进一步阐明脑血管疾病和AD影响认知功能下降的机制对于全面理解AD神经退变的发生和发展有着重要的意义,将为AD的预防和治疗提供新的思路。

阿尔茨海默病；脑血管疾病；脑淀粉样血管病；认知损害

长期以来,脑血管疾病(Cerebrovascular Disease,CVD)与阿尔茨海默病(Alzheimer′s Disease,AD)之间的联系是大家所关注的话题。随着年龄的增长,AD和脑血管病的发病率均增加,能引起脑血管病的危险因素也同样能促发AD,除了衰老这一重要因素外,高血压、吸烟、高血脂、糖尿病、同型半胱氨酸、ApoE4基因亚型、动脉粥样硬化等都是它们共同的危险因素[1-2]。最近研究显示,脑血管疾病在AD的发病机制中发挥重要的作用,有的研究者甚至认为AD是一种脑血管性疾病而不是神经退行性疾病[3-5]。

1　脑血管疾病在衰老过程中常见类型及对AD的影响

衰老使AD和脑血管疾病的发病率均增加。最近研究显示,老年人中脑血管病明显增加了AD发生的危险性,尤其是在疾病的早期可进一步强化阿尔茨海默病样病理改变的作用,进而促进痴呆的发生并使其程度加重[6]。特别是在AD的初期阶段,脑血管病变可影响和加重认知功能障碍,降低临床痴呆发生的阈值[7-8]。

老年人脑血管病变的类型主要包括:脑淀粉样血管病(CAA),脑动脉粥样硬化,小血管疾病(在大多数情况下由高血压引起,即高血压血管病变),或微血管退变(迂曲、纤维化和脂质透明变性),血脑屏障(BBB)功能障碍引起的脑白质病变(WMLs),微型脑梗死,腔隙或腔隙性梗死,颅内微型出血等等。所有这些病症可能会破坏脑血管的完整性,并改变脑灌注导致神经元损伤和认知功能障碍。有大量数据支持AD患者脑内存在不同程度的脑血管病变,如Kalaria和Ballard[9]通过300例AD患者的尸检结果表明,98%患者脑内有脑淀粉样血管病变(Cerebral Amyloid Angiopathy,CAA),100%存在不同程度的微血管退行性病变,31%有不同程度的脑梗死和7%患者有颅内出血。而Olichney[10]在248例AD患者的尸检结果也显示,48%有脑血管损伤,31%患者伴有微型脑梗死,12.5%患者有大型脑梗死和13.5%有颅内出血。通过比较173例AD患者和130例正常老年人结果显示,脑血管损伤在AD患者所占比率(56.4%)明显比正常对照高(42.4%)[11]。这些研究表明,脑血管病在AD的发生和发展方面起着很大的作用。最近通过对来源于国际阿尔茨海默病协调中心(National Alzheimer′s Coordinating Center,NACC)数据库的5715例患者评估,确认了脑血管病变在AD患者中的发病率,揭示它们可能在影响认知功能下降方面具有相加或协同作用[12-14]。然而,它们影响认知功能的结合作用具体机制尚不明确,而且在流行病学和临床病理研究得出的结果显示它们之间的相互关系尚存争议[15-19]。

2　脑血管疾病影响阿尔茨海默病的机制

传统理论认为脑血管病变仅与血管性痴呆(Vascular Dementia,VD)相关,上面的AD与脑血管病关系的证据说明脑血管病在AD的发生和发展方面起着很大的作用,其联系机制可能有以下几点:

2.1脑组织血流灌注障碍大量研究表明,慢性脑组织低灌注可导致区域性突触前和突触后改变、蛋白合成异常及能量代谢调节障碍、葡萄糖利用减少、胆碱能受体丧失,也可促发海马区微血管病变及其辐射神经元损伤[20]。区域性低灌注在散发性及家族性AD中均为较早期的发现,AD患者的局部脑血流确有明显下降。另外,目前改善AD认知水平的治疗药物如胆碱酯酶抑制剂也能通过增加脑灌注改善病情[21-22]。

脑血管疾病已被证明能诱导β淀粉样蛋白(Aβ)的沉积,小血管病变导致血脑屏障结构和功能上的破坏,引起ApoE蛋白从脑内泄漏和Aβ在脑血管周围的星型胶质细胞聚集[23],导致Aβ的沉积[24]。这种沉积也会造成脑内微血管退行性病变,导致脑血流灌注障碍。而且脑血管疾病也会造成血脑屏障破坏和脑内淀粉样蛋白主要成分Aβ的代谢障碍,加重血管壁淀粉样沉积,进一步加重血管腔的狭窄和供血障碍,形成恶性循环[25]。慢性脑组织低灌注可以通过影响脑内能量代谢,减低三磷酸腺苷(ATP)合成和产生氧自由基,引起神经元损伤而加重神经元缺失。ATP合成降低会激活相关蛋白激酶,导致tau蛋白异常磷酸化,并使tau蛋白的翻译后修饰过程异常[26]。

2.2血管新生异常在AD患者脑中存在血管新生异常,表现为毛细血管密度减小和脑内皮细胞壁退化。Bell等报道AD患者6个脑区域的毛细血管密度比正常对照组少17%左右,其中在距状裂皮质区域减少18%[27]。Bailey等[28]研究表明,脑内毛细血管密度的降低与AD患者临床痴呆程度相关。但也有研究表明,AD脑内某些局部区域毛细血管密度增高[29]。

脑内血管新生是在已有血管的基础上通过刺激内皮细胞的增殖、迁移和骨髓衍生细胞异质群(包括EPCs、周祖细胞等)的募集。EPCs掺入脉管系统分化为内皮细胞,而PPCs发育成熟为周细胞和血管平滑肌细胞。正常情况下,脑内缺氧会调节缺氧诱导因子-1(HIF-1)的表达诱导血管的新生,该过程主要通过血管内皮生长因子(VEGF)来实现;而当VEGF不足时,血管细胞凋亡[30]。有研究指出,AD患者大脑血管密度异常可能与Aβ的聚集有关,虽然在AD患者VEGF水平增高,但Aβ与VEGF因子结合沉积在淀粉样斑块中,从而导致AD病理过程中的神经退行性病变以及抑制血管新生[31]。在AD发病早期,VEGF表达增加可对抗血管缺乏和低灌注。但随着AD的发展,VEGF不断在Aβ斑块周围沉积,VEGF与Aβ斑块紧密结合,最终导致局部VEGF缺乏,损伤其神经保护功能即血管再生。异常血管生成或内皮老化引起Aβ清除受体(LRP)水平降低或流入受体RAGE水平增加将导致Aβ在血脑屏障不完全清除[32]。同时,缺氧引起血管生成素-2(Ang-2)水平升高,占领Tie-2受体,阻止血管生成素-1(Ang-1)与它结合,导致毛细血管周细胞游离出来,影响毛细血管的稳定性,破坏血脑屏障[33]。

2.3炎性反应异常越来越多的实验和临床证据表明,在AD的发生发展过程中,始终伴随着慢性炎性反应,多种胶质细胞及炎性反应因子参与其中的炎性反应损伤病理过程。脑血管疾病中,损伤的脑血管壁细胞(特别是血管内皮细胞)激发炎性反应,释放大量炎性反应因子损伤神经细胞。AD脑内微血管释放大量的促炎因子,如一氧化氮(NO)、凝血酶(thrombin)、肿瘤坏死因子a(TNF-a)、转化生长因子β(TGF-β)、白介素1β(IL-1β)、IL-6、IL-8和基质金属蛋白酶(MMPs)等[34],这些炎性反应因子水平比正常人脑血管内含量明显升高。体外实验结果也表明,AD患者来源的微血管与神经元共培养出现明显的神经毒性,而与正常微血管培养表现的神经毒性明显减少或无毒性[35]。这种神经毒性可能与脑血管内皮细胞功能障碍有关,有研究表明,应用促炎因子IL-1β和LPS刺激脑血管内皮细胞释放的因子能杀死胆碱能神经元[36]。

而且炎性反应和氧化应急损伤脑内皮细胞还能诱导产生神经毒性蛋白酶-凝血酶(thrombin)。在AD脑内thrombin及其受体PAR-1水平显著升高,它是老年斑淀粉样沉淀的成份[37]。thrombin能通过直接和间接的途径对神经元产生毒性作用,研究表明它能刺激小胶质细胞的JAK2-STAT3信号通路增加TNF-a和诱导型NO表达[38],还能通过调节星型胶质细胞ERK1/2信号通路增加MMP-9表达[39]。它还通过影响神经元细胞周期、促凋亡和NADPH氧化酶介导的氧化应激等发挥直接神经毒性,脑室内直接给予thrombin导致神经细胞死亡和认知功能障碍[40]。同时,研究发现蛋白酶nexin-1(thrombin抑制剂)活性在AD脑内,特别是脑血管周围显著减少,说明thrombin主要从血管释放[41]。

3　结论

传统观点认为,AD疾病进程的起始因素是神经元退变,神经血管病理变化是神经元损伤后的继发事件。然而,单纯的神经元功能紊乱仅能影响神经活动引起脑血流灌注的变化,并不能引起中枢动脉粥样硬化,软膜和脑内动脉血管生成,血管老化和微血管病理改变,不能引发脑血管炎性反应、BBB转运体缺陷或者发生在AD的血管修复。虽然目前不能确定脑血管病变是影响AD的发生还是发展,但是它确实在AD的神经元功能紊乱中起重要作用。它们之间的联系机制的阐明对于全面理解AD神经退变的发生和发展有着重要的意义,将为AD的预防和治疗提供新的思路。

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(2016-04-10收稿责任编辑：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

国家自然科学基金青年项目(编号: 81202794)——“特异性蛋白质相互作用网络在脑梗死发生中的作用及中药脑泰方干预机制研究”

王国佐(1978.08—)，男，在读博士研究生，副教授，研究方向：中西医结合防治心脑血管疾病研究，E-mail:1586074663@qq.com

成绍武(1976.02—)，男，博士后，教授，湖南中医药大学中西医结合防治心脑血管疾病湖南省重点实验室副主任，研究方向:衰老神经生物学与中药抗衰老，E-mail:docshwcheng@hotmail.com

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