Acta Neuropathologica: 粗粒斑块:早发型阿尔茨海默病中一种不同的Aβ斑块类型

2020-09-19 MedSci原创 MedSci原创

阿尔茨海默病(AD)以β淀粉样蛋白(Aβ)沉积为特征,其形态多样,临床意义各异。

淀粉样β(Aβ)斑块和高磷酸化tau(pTau)缠结是阿尔兹海默病(AD)的主要病理特征。Aβ斑块起源于Aβ肽的积累和聚集,是由β-分泌酶和γ-分泌酶连续裂解淀粉样前体蛋白而形成的。根据γ-分泌酶的裂解位点,Aβ肽的长度可能在36到43个氨基酸之间不等,其中Aβ40和Aβ42是AD中最常见的形式。较长的Aβ42更容易聚集,主要存在于脑实质斑块中,而较短的Aβ40由较高水平的细胞分泌,是沉积在脑血管系统中的主要Aβ亚型,称为脑淀粉样血管病(CAA)。

以前,我们观察到一种非典型的Aβ沉积,称为粗粒斑块。在这项研究中,我们评估了斑块与临床疾病的关系,并进行了深入的免疫组化和形态学鉴定。粗粒斑块是一种相对较大的沉积物,其特征是具有多核和无Aβ样孔隙,在新皮质中非常突出。对74例(n=74)Aβ阳性患者额叶中回的斑块进行半定量评分,包括非痴呆患者(n=15)、早发型(EO)AD(n=38)和晚发型(LO)AD(n=21)。粗颗粒斑块仅在临床痴呆患者中观察到,与LOAD相比,在EOAD中更常见。该斑块与纯合APOE ε4状态和脑淀粉样血管病(CAA)有关。通过研究粗颗粒斑块的神经炎性成分(pTau、APP、PrPC)、Aβ亚型成分(Aβ40、Aβ42、AβN3pE、pSer8Aβ)、其神经炎症成分(C4b、CD68、MHC-II、GFAP)及其血管属性(层粘连蛋白、IV型胶原、norrin)进行了深入表征。将斑块与经典的核心斑块、棉絮斑块和CAA进行比较。与CAA相似,但不同于经典的核心斑块,粗粒斑块主要由Aβ40组成。此外,粗颗粒斑块与强烈的神经蛋白炎症和血管(毛细血管)病理学明显相关。共焦激光扫描显微镜(CLSM)和3D分析显示,大多数粗粒斑块具有特殊的Aβ40壳层结构,并且与血管直接相关。根据其形态和生化特征,我们认为粗粒斑块是一种与EOAD相关的发散型Aβ斑块。粗颗粒斑块与其他Aβ沉积的区别可能是由于Aβ的加工和聚集、神经炎症反应和血管清除的差异。在寻找以疾病机制为基础的治疗方法中,分离AD亚组间特异性Aβ沉积可能是很重要的。

方法:对苏木精和伊红(H&E)、刚果红、Aβ(aa 8-17)、Aβ40、Aβ42、AβN3pE、pSer8Aβ、APP、PrPC、pTau、C4b、MHC-II、GFAP、norrin、层粘连蛋白、IV型胶原和载脂蛋白E的连续切片进行免疫组织化学。用苏木精浸泡切片(5min),然后用伊红(3min)浸泡切片进行H&E。刚果红的组织化学是在室温下用饱和氯化钠溶液(3%氯化钠在80%乙醇和1% 1 M NaOH中)孵育,然后用饱和刚果红溶液(0.25%刚果红溶于80%乙醇和1% 1 M NaOH)孵育,两种方法均在室温下进行20分钟。内源性过氧化物酶用0.3%H2O2在磷酸盐缓冲液(PBS;ph7.4)或甲醇中猝灭。随后进行适当的抗原回收和初级抗体培养。随后,用二级抗体培养切片,然后用3,3'-二氨基联苯胺(DAB)(安捷伦达科)显色并用苏木精复染。在两个步骤之间,用PBS冲洗切片。

总而言之,在本研究中,我们描述并定义了一种新类型的Aβ沉积,称为"粗粒斑块"。我们提供了粗粒斑块的形态学和生物化学定义,支持这种沉积是独特的,具有特定的临床和病因学联系。相关的疾病机制如神经炎症和血管属性,以及Aβ的结构和生化组成可能是Aβ沉积形态差异的原因。在不远的将来,分离AD亚群间的特异性Aβ沉积可能对寻找基于疾病机制的治疗方法具有重要意义。

Boon, B.D.C., Bulk, M., Jonker, A.J. et al. The coarse-grained plaque: a divergent Aβ plaque-type in early-onset Alzheimer’s disease. Acta Neuropathol (2020)

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  4. 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  5. 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createdAvatar=http://thirdqq.qlogo.cn/qqapp/101296147/4E6244DB7C1860858424437821E08291/100, createdBy=a6a52500039, createdName=ms3994565386320060, createdTime=Mon Sep 21 07:29:54 CST 2020, time=2020-09-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1470409, encodeId=897814e040918, content=<a href='/topic/show?id=45a79e7788c' target=_blank style='color:#2F92EE;'>#阿尔茨海默#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=21, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97778, encryptionId=45a79e7788c, topicName=阿尔茨海默)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c5917090900, createdName=yhj-time, createdTime=Mon Sep 21 07:29:54 CST 2020, time=2020-09-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1605269, encodeId=b57e1605269fb, content=<a href='/topic/show?id=b820309108' target=_blank style='color:#2F92EE;'>#Aβ#</a>, beContent=null, objectType=article, 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    2021-07-26 windight
  6. 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  7. 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  8. [GetPortalCommentsPageByObjectIdResponse(id=1818055, encodeId=613d1818055fc, content=<a href='/topic/show?id=4c9f9e777ac' target=_blank style='color:#2F92EE;'>#阿尔茨海#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=39, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97777, encryptionId=4c9f9e777ac, topicName=阿尔茨海)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=636e2500187, createdName=12498da4m32(暂无昵称), createdTime=Tue Jun 22 08:29:54 CST 2021, time=2021-06-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1786392, encodeId=a6881e863926f, content=<a href='/topic/show?id=569f13e9045' target=_blank style='color:#2F92EE;'>#Pathol#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=22, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=13790, encryptionId=569f13e9045, topicName=Pathol)], attachment=null, authenticateStatus=null, createdAvatar=, 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  9. 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    2020-09-21 膀胱癌

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