Longitudinal, quantitative assessment of amyloid, neuroinflammation, and anti-amyloid treatment in a living mouse model of Alzheimer's disease enabled by positron emission tomography
Longitudinal, quantitative assessment of amyloid, neuroinflammation, and anti-amyloid treatment in a living mouse model of Alzheimer's disease enabled by positron emission tomography
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DOI：
10.1523/jneurosci.0673-07.2007
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发表时间：
2007-10-10
影响因子：
5.3
通讯作者：
Suhara, Tetsuya
中科院分区：
文献类型：
--
作者：
Maeda, Jun;Ji, Bin;Suhara, Tetsuya
我们为高分辨率正电子发射断层扫描（PET）成像系统在活的淀粉样蛋白前体转基因（Tg）小鼠中定量绘制淀粉样蛋白积累的能力提供了第一个证据。静脉注射具有高特异性放射性的N-[C-11]甲基-2-（4'-甲基氨基苯基）-6-羟基苯并噻唑（或匹兹堡化合物b的[C-11] PIB）后，Tg小鼠在富含淀粉样蛋白的区域表现出高水平的放射性保留。对Tg小鼠进行的PET研究，包括纵向评估，显示了放射性配体结合的年龄依赖性增加，与淀粉样蛋白的进行性积累一致。在使用抗淀粉样蛋白肽（A β）抗体进行抗淀粉样蛋白治疗的过程中，通过多次PET扫描也成功地监测了Tg小鼠海马中淀粉样蛋白水平的降低。此外，用[F-18]氟乙基- daa1106（一种活化胶质细胞的放射性示踪剂）对这些个体进行PET扫描，与淀粉样蛋白成像同时进行，揭示了治疗诱导的神经炎症反应，其强度与[C-11]PIB估计的预先存在的淀粉样蛋白水平密切相关。同样值得注意的是，在阿尔茨海默病（AD）和Tg小鼠大脑中，[11C] PIB放射自显像信号的定位和丰度与N末端截断和修饰的A β、A β n3 -焦谷氨酸密切相关，这表明[11C] PIB正电子发射断层扫描对淀粉样蛋白的检测依赖于特异性A β亚型的积累。我们的研究结果支持小动物专用PET系统与高特异性放射性探针和适当的Tg模型相结合的有效性，不仅可以阐明小鼠模型中淀粉样变性的机制特性，还可以用于新出现的AD诊断和治疗方法的临床前测试。
We provide the first evidence for the capability of a high-resolution positron emission tomographic ( PET) imaging system in quantitatively mapping amyloid accumulation in living amyloid precursor protein transgenic (Tg) mice. After the intravenous administration of N-[C-11] methyl-2-(4'-methylaminophenyl)-6-hydroxybenzothiazole ( or [C-11] PIB for "Pittsburgh Compound-B") with high-specific radioactivity, the Tg mice exhibited high-level retention of radioactivity in amyloid-rich regions. PET investigation for Tg mice over an extended range of ages, including longitudinal assessments, demonstrated age-dependent increase in radioligand binding consistent with progressive amyloid accumulation. Reduction in amyloid levels in the hippocampus of Tg mice was also successfully monitored by multiple PET scans along the time course of anti-amyloid treatment using an antibody against amyloid beta peptide (A beta). Moreover, PET scans with [F-18]fluoroethyl-DAA1106, a radiotracer for activated glia, were conducted for these individuals parallel to amyloid imaging, revealing treatment-induced neuroinflammatory responses, the magnitude of which intimately correlated with the levels of pre-existing amyloid estimated by [C-11]PIB. It is also noteworthy that the localization and abundance of [ 11C] PIB autoradiographic signals were closely associated with those of N- terminally truncated and modified A beta, A beta N3-pyroglutamate, in Alzheimer's disease ( AD) and Tg mouse brains, implying that the detectability of amyloid by [ 11C] PIB positron emission tomography is dependent on the accumulation of specific A beta subtypes. Our results support the usefulness of the small animal-dedicated PET system in conjunction with high-specific radioactivity probes and appropriate Tg models not only for clarifying the mechanistic properties of amyloidogenesis in mouse models but also for preclinical tests of emerging diagnostic and therapeutic approaches to AD.