Department of Alzheimer's Disease Research, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, 36-3, Gengo, Morioka, Obu, Aichi 474-8522, Japan.
Brain Res. 2010 Feb 22;1315:137-49. doi: 10.1016/j.brainres.2009.12.005. Epub 2010 Jan 8.
We elucidated how Alzheimer-type pathologies of amyloid beta-protein (Abeta) and tau spatiotemporally emerge in brains of nontransgenic nonhuman primate, cynomolgus monkey, in the present study. To examine the accumulation of deposited Abeta, phosphorylated tau accumulation, intracellular tau accumulation, and neurofibrillary tangle formation, the brains, mainly temporal cortex and hippocampus, of 34 cynomolgus monkeys aged 6 to 36 years were studied by biochemical and histochemical analyses. Biochemically, first, the accumulation of insoluble Abeta was detected in the neocortical (temporal and frontal) and hippocampal regions of animals as young as mid-20s and their levels were extremely high in those of advanced age. The accumulation of phosphorylated tau in the same regions occurred before the age of 20 with poor correlation to the levels of insoluble Abeta. Histologically, intraneuronal and intraoligodendroglial tau accumulation was observed in temporal cortex and hippocampus of animals before the age of 20. In an advanced aged 36-year-old individual, argyrophilic tangles and tau-accumulated dystrophic neurites were markedly observed in the medial temporal area contiguous to limbic structures. Notably, these tau pathologies also emerged, to a lesser extent, in the temporal cortices of advanced aged animals harboring significant amounts of insoluble Abeta. These results suggest that the cynomolgus monkey can be used to elucidate the age-dependent sequence of Abeta and tau pathologies.
在本研究中，我们阐明了阿尔茨海默病样淀粉样β蛋白（Abeta）和tau 的病理在非转基因非人灵长类动物恒河猴大脑中的时空出现方式。为了研究沉积 Abeta 的积累、磷酸化 tau 的积累、细胞内 tau 的积累和神经纤维缠结的形成，我们通过生化和组织化学分析研究了 34 只年龄在 6 至 36 岁的恒河猴的大脑，主要是颞叶皮质和海马区。从生物化学上看，首先，在 20 多岁的动物的新皮质（颞叶和额叶）和海马区检测到不溶性 Abeta 的积累，其水平在老年动物中极高。同一区域磷酸化 tau 的积累发生在 20 岁之前，与不溶性 Abeta 的水平相关性较差。组织学上，在 20 岁之前，在颞叶皮质和海马区观察到神经元内和少突胶质细胞内 tau 的积累。在一个 36 岁的老年个体中，在与边缘结构相邻的内侧颞叶区域明显观察到银染缠结和 tau 积累的退行性神经突。值得注意的是，这些 tau 病理学也在颞叶皮质中出现，程度较轻，在颞叶皮质中积累了大量不溶性 Abeta 的老年动物中。这些结果表明，恒河猴可用于阐明 Abeta 和 tau 病理学的年龄依赖性序列。
