Pharmacological removal of serum amyloid P component from intracerebral plaques and cerebrovascular Aβ amyloid deposits in vivo
Pharmacological removal of serum amyloid P component from intracerebral plaques and cerebrovascular Aβ amyloid deposits in vivo
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DOI：
10.1098/rsob.150202
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发表时间：
2016-02-01
期刊：
影响因子：
5.8
通讯作者：
Pepys, Mark B.
中科院分区：
文献类型：
--
作者：
Al-Shawi, Raya;Tennent, Glenys A.;Pepys, Mark B.
人淀粉样蛋白沉积物总是含有正常血浆蛋白血清淀粉样蛋白P组分（SAP），这是由于其与所有淀粉样蛋白原纤维（包括阿尔茨海默病（AD）和脑淀粉样血管病（CAA）的脑实质斑块和脑血管淀粉样蛋白沉积物中的淀粉样蛋白β（A β）原纤维）的亲和但可逆的结合。SAP在体外促进淀粉样蛋白原纤维形成，有助于淀粉样蛋白在体内的持续存在，并且本身也对脑神经元直接有毒。因此，我们开发了（R）-1-[6-[（R）-2-羧基-吡咯烷-1-基（-6-氧代-己酰基）]吡咯烷-2-羧酸（CPHPC），这是一种从AD患者血液中清除SAP的药物，从而也从脑脊液（CSF）中清除SAP。在这里，我们报告说，在TASTPM双转基因AD小鼠模型中引入转基因人SAP表达后，所有淀粉样蛋白沉积物均含有人SAP。通过在这些小鼠中施用CPHPC消耗循环人SAP，从脑内和脑血管淀粉样蛋白中去除所有可检测的人SAP。证明从血液和CSF中去除SAP也将其从这些淀粉样蛋白沉积物中去除，这一点至关重要地验证了即将进行的CPHPC临床试验“阿尔茨海默病中血清淀粉样蛋白P组分的消耗（DESPIAD）”的策略。该结果也有力地支持了CPHPC在CAA患者中的临床试验。
Human amyloid deposits always contain the normal plasma protein serum amyloid P component (SAP), owing to its avid but reversible binding to all amyloid fibrils, including the amyloid beta (A beta) fibrils in the cerebral parenchyma plaques and cerebrovascular amyloid deposits of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). SAP promotes amyloid fibril formation in vitro, contributes to persistence of amyloid in vivo and is also itself directly toxic to cerebral neurons. We therefore developed (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl(-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC), a drug that removes SAP from the blood, and thereby also from the cerebrospinal fluid (CSF), in patients with AD. Here we report that, after introduction of transgenic human SAP expression in the TASTPM double transgenic mouse model of AD, all the amyloid deposits contained human SAP. Depletion of circulating human SAP by CPHPC administration in these mice removed all detectable human SAP from both the intracerebral and cerebrovascular amyloid. The demonstration that removal of SAP from the blood and CSF also removes it from these amyloid deposits crucially validates the strategy of the forthcoming 'Depletion of serum amyloid P component in Alzheimer's disease (DESPIAD)' clinical trial of CPHPC. The results also strongly support clinical testing of CPHPC in patients with CAA.