阿尔兹海默病非人灵长类模型建立和多病理生理特征之间关系研究

To date, the failure of clinical trials against Alzheimer's disease (AD) that try to modify the disease can be attributed two main causes: 1. The relationship among multiple pathophysiological features of AD remains elusive. 2. There is a huge gap in pathophysiological feature between human AD and animal models mainly represented by rodent models used in pre-clinical studies of AD drug development. Old common marmoset can spontaneously generate brain β-amyloid (Aβ) plaques and has the condition to prepare non-human primate model of AD and to study the relationship among brain Aβ deposition, Tau hyperphosphorylation, glucose hypometabolism, neuroinflammation, and cognitive impairment. Our preliminary study found that the level and distribution of brain Aβ deposition in 5-8 years old marmoset kept long-term stable under general feeding and exhibited significant enhancement after 4 months treatment of pyrithiamine, a antagonist of thiamine. In this project, we will repress thiamine metabolism of marmoset by administering pyrithiamine and strengthen thiamine metabolism of marmoset by administering benfotiamine, a liposoluble derivative of thiamine. Then, the relationship among brain Aβ deposition, Tau hyperphosphorylation, glucose hypometabolism, neuroinflammation, and cognitive impairment will be investigated by Aβ-, Tau-, FDG-PET scanning and biochemical assay of cerebrospinal fluid. The results will fill in the blank of batch production and longitudinal study of AD nonhuman primate models as well as promote the understanding of AD pathogenesis.

阿尔兹海默病（AD）多病理生理特征之间关系仍不清晰、目前用于AD新药研发的小鼠模型等与人类疾病特征相距甚远、存在巨大鸿沟是AD新药研发屡遭失败的主要原因。狨猴在老年期可自发产生脑β-淀粉样蛋白（Aβ）斑块，具有制备与人类AD疾病特征相似的非人灵长类疾病模型、开展各病理生理特征之间关系研究的条件。我们前期利用Aβ-PET等研究发现，硫胺素拮抗剂吡啶硫胺处理5-8岁狨猴4个月能显著增加狨猴脑Aβ沉积。本课题计划利用5-8岁狨猴，通过吡啶硫胺阻遏和硫胺素衍生物苯磷硫胺促进硫胺素代谢，结合β-分泌酶抑制剂处理，利用Aβ/Tau/2-脱氧葡萄糖-PET在体检测和脑脊液生化检测炎性因子等手段，研究狨猴脑Aβ沉积、Tau异常磷酸化、葡萄糖代谢异常、神经炎症等AD主要病理生理特征之间关系，及其与认知功能改变、疾病进展之间的关系，填补可批量生产和纵向研究AD非人灵长类模型的空白，促进对AD发病机制的理解。

阿尔兹海默病（AD）多病理生理特征之间关系仍不清晰、目前用于AD新药研发的小鼠模型等与人类疾病特征相距甚远、存在巨大鸿沟是AD新药研发屡遭失败的主要原因。我们研究结果表明狨猴在老年期可自发产生脑β-淀粉样蛋白（Aβ）斑块，苯磷硫胺能够改善老年狨猴的认知水平，并与升高的Aβ水平呈正相关。硫胺素拮抗剂吡啶硫胺处理5-8岁狨猴4个月能显著增加狨猴脑Aβ沉积。对AD脑硫胺素代谢障碍机制进一步研究发现硫胺素焦磷酸激酶(thiamine pyrophosphokinase, TPK)的表达在AD病人中特异性下降。TPK条件性敲除小鼠能够模拟所有人类AD疾病的重要多病理生理。同时上调TPK能够提高脑TDP代谢水平。调控狨猴TPK有望可批量生产和纵向研究AD非人灵长类模型，促进对AD发病机制的理解。