In-vivo visualization of key molecular processes involved in Alzheimer's disease pathogenesis: Insights from neuroimaging research in humans and rodent models.
In-vivo visualization of key molecular processes involved in Alzheimer's disease pathogenesis: Insights from neuroimaging research in humans and rodent models.
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DOI：
10.1016/j.bbadis.2010.01.003
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发表时间：
2010-04
期刊：
影响因子：
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通讯作者：
M. Higuchi;J. Maeda;Bin Ji;M. Maruyama;T. Okauchi;M. Tokunaga;M. Ono;T. Suhara
中科院分区：
文献类型：
--
作者：
M. Higuchi;J. Maeda;Bin Ji;M. Maruyama;T. Okauchi;M. Tokunaga;M. Ono;T. Suhara
各种年龄相关的神经退行性疾病在分子水平上以自聚集分子的沉积为特征，如阿尔茨海默病中的淀粉样β肽（Aβ）和tau蛋白，并且级联型链式反应被认为是从这些淀粉样成分的生化异常开始的。编码Aβ、tau蛋白和其他致病起始物的基因的突变和增殖可能会加速级联顶端的初始过程，从而使这些疾病的转基因和基因敲入动物模型的世代合理化。同时，这些遗传操作并不一定会压缩连接淀粉样蛋白生成和神经元致死性的关键中间事件的时间线，从而导致疾病的不完全重演。对整个级联建模的要求可以通过人类和动物模型的并排比较来说明，并借助通常适用于不同物种的基于成像的生物标志物。值得注意的是，在一个高度反应性的状态下的关键组件是由正电子发射断层扫描（PET）为例的探针辅助神经成像技术进行分析，提供关键信息，这些目标分子的体内可及性。事实上，多物种PET研究结合生物化学、电生理学和神经病理学测试已经揭示了Aβ组装体的推定神经毒性亚种、在侵袭性但非神经保护性小胶质细胞中积累的转运蛋白以及内源性神经递质和外源性激动性配体可利用的功能活性神经受体。基于这种实验范式的人类病例和模型菌株之间的双向翻译研究目前旨在阐明tau的发病机制，并将扩展到钙稳态破坏和线粒体损伤的分析。由于关键过程之间的相互因果关系已经表明级联和网络连接之间的结构相似性作为病因学表征，因此具有从上到下覆盖级联的多个探针的纵向成像测定实际上描绘了在疾病及其治疗过程中不断改变的网络动态，并因此加快了用于在其全长上抑制神经变性途径的治疗策略的评估和优化。
Diverse age-associated neurodegenerative disorders are featured at a molecular level by depositions of self-aggregating molecules, as represented by amyloid β peptides (Aβ) and tau proteins in Alzheimer's disease, and cascade-type chain reactions are supposedly commenced with biochemical aberrancies of these amyloidogenic components. Mutagenesis and multiplication of the genes encoding Aβ, tau and other pathogenic initiators may accelerate the incipient process at the cascade top, rationalizing generations of transgenic and knock-in animal models of these illnesses. Meanwhile, these genetic manipulations do not necessarily compress the timelines of crucial intermediate events linking amyloidogenesis and neuronal lethality, resulting in an incomplete recapitulation of the diseases. Requirements for modeling the entire cascade can be illustrated by a side-by-side comparison of humans and animal models with the aid of imaging-based biomarkers commonly applicable to different species. Notably, key components in a highly reactive state are assayable by probe-assisted neuroimaging techniques exemplified by positron emission tomography (PET), providing critical information on the in-vivo accessibility of these target molecules. In fact, multispecies PET studies in conjunction with biochemical, electrophysiological and neuropathological tests have revealed putative neurotoxic subspecies of Aβ assemblies, translocator proteins accumulating in aggressive but not neuroprotective microglia, and functionally active neuroreceptors available to endogenous neurotransmitters and exogenous agonistic ligands. Bidirectional translational studies between human cases and model strains based on this experimental paradigm are presently aimed at clarifying the tau pathogenesis, and would be expanded to analyses of disrupted calcium homeostasis and mitochondrial impairments. Since reciprocal causalities among the key processes have indicated an architectural interchangeability between cascade and network connections as an etiological representation, longitudinal imaging assays with manifold probes covering the cascade from top to bottom virtually delineate the network dynamics continuously altering in the course of the disease and its treatment, and therefore expedite the evaluation and optimization of therapeutic strategies intended for suppressing the neurodegenerative pathway over its full length.