In vitro characterization of Pittsburgh compound-B binding to Lewy bodies
In vitro characterization of Pittsburgh compound-B binding to Lewy bodies
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DOI：
10.1523/jneurosci.0630-07.2007
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发表时间：
2007-09-26
影响因子：
5.3
通讯作者：
Villemagne, Victor L.
中科院分区：
文献类型：
--
作者：
Fodero-Tavoletti, Michelle T.;Smith, David P.;Villemagne, Victor L.
路易体痴呆的病理特征是在新皮质、边缘和边缘旁区域出现含有α-突触核蛋白的路易小体。像阿尔茨海默病(AD)一样，Aβ斑块也存在于大多数DLB病例中。Aβ对DLB的发展的贡献尚不清楚。[C-11]-匹兹堡化合物B([C-11]-PIB)是一种硫代黄素-T衍生物，可以使用正电子发射断层扫描(PET)来定量体内的Aβ负荷。[11C]-PIB PET研究表明，AD和DLB受试者的皮质[C-11]-PIB结合率类似。为了在DLB患者中确定PIB与α-突触核蛋白的潜在结合，我们研究了PIB与重组人α-突触核蛋白和DLB脑匀浆的体外结合。体外结合研究分析表明，[H-3]-PIB与α-突触核蛋白纤维结合，但亲和力低于Aβ(1-42)纤维的亲和力。此外，观察到[H-3]-PIB能与含有Aβ斑块的DLB脑匀浆结合，但不能与无Aβ斑块的DLB匀浆结合。DLB脑切片PIB荧光染色阳性，与免疫反应阳性的Aβ斑块共存，未见路易小体染色。此外，图像量化分析表明，考虑到DLB受试者大脑中路易体的小尺寸和低密度，路易体对[11C]-PIB PET信号的任何贡献都可以忽略不计。这些研究表明，在[11C]-PIB PET研究中观察到的DLB受试者皮质灰质区内的PIB滞留主要归因于PIB与Aβ斑块的结合，而不是路易小体。
Dementia with Lewy bodies ( DLB) is pathologically characterized by the presence of alpha-synuclein-containing Lewy bodies within the neocortical, limbic, and paralimbic regions. Like Alzheimer's disease ( AD), A beta plaques are also present in most DLB cases. The contribution of A beta to the development of DLB is unclear. [C-11]-Pittsburgh compound B ([C-11]-PIB) is a thioflavin-T derivative that has allowed in vivo A beta burden to be quantified using positron emission tomography ( PET). [ 11C]-PIB PET studies have shown similar high cortical [C-11]-PIB binding in AD and DLB subjects. To establish the potential binding of PIB to alpha-synuclein in DLB patients, we characterized the in vitro binding of PIB to recombinant human alpha-synuclein and DLB brain homogenates. Analysis of the in vitro binding studies indicated that [H-3]-PIB binds to alpha-synuclein fibrils but with lower affinity than that demonstrated/ reported for A beta(1-42) fibrils. Furthermore, [H-3]-PIB was observed to bind to A beta plaque-containing DLB brain homogenates but failed to bind to DLB homogenates that were A beta plaque-free ("pure DLB"). Positive PIB fluorescence staining of DLB brain sections colocalized with immunoreactive A beta plaques but failed to stain Lewy bodies. Moreover, image quantification analysis suggested that given the small size and low density of Lewy bodies within the brains of DLB subjects, any contribution of Lewy bodies to the [ 11C]-PIB PET signal would be negligible. These studies indicate that PIB retention observed within the cortical gray matter regions of DLB subjects in [ 11C]-PIB PET studies is largely attributable to PIB binding to A beta plaques and not Lewy bodies.