Okabayashi Sachi, Shimozawa Nobuhiro, Yasutomi Yasuhiro, Yanagisawa Katsuhiko, Kimura Nobuyuki
Tsukuba Primate Research Center, National Institute of Biomedical Innovation, 1-1 Hachimandai, Tsukuba-shi, Ibaraki, 305-0843, Japan; The Corporation for Production and Research of Laboratory Primates, 1-1 Hachimandai, Tsukuba-shi, Ibaraki, 305-0843, Japan.
Tsukuba Primate Research Center, National Institute of Biomedical Innovation, 1-1 Hachimandai, Tsukuba-shi, Ibaraki, 305-0843, Japan.
PLoS One. 2015 Feb 12;10(2):e0117362. doi: 10.1371/journal.pone.0117362. eCollection 2015.
Growing evidence suggests that diabetes mellitus (DM) is one of the strongest risk factors for developing Alzheimer's disease (AD). However, it remains unclear why DM accelerates AD pathology. In cynomolgus monkeys older than 25 years, senile plaques (SPs) are spontaneously and consistently observed in their brains, and neurofibrillary tangles are present at 32 years of age and older. In laboratory-housed monkeys, obesity is occasionally observed and frequently leads to development of type 2 DM. In the present study, we performed histopathological and biochemical analyses of brain tissue in cynomolgus monkeys with type 2 DM to clarify the relationship between DM and AD pathology. Here, we provide the evidence that DM accelerates Aβ pathology in vivo in nonhuman primates who had not undergone any genetic manipulation. In DM-affected monkey brains, SPs were observed in frontal and temporal lobe cortices, even in monkeys younger than 20 years. Biochemical analyses of brain revealed that the amount of GM1-ganglioside-bound Aβ (GAβ)--the endogenous seed for Aβ fibril formation in the brain--was clearly elevated in DM-affected monkeys. Furthermore, the level of Rab GTPases was also significantly increased in the brains of adult monkeys with DM, almost to the same levels as in aged monkeys. Intraneuronal accumulation of enlarged endosomes was also observed in DM-affected monkeys, suggesting that exacerbated endocytic disturbance may underlie the acceleration of Aβ pathology due to DM.
越来越多的证据表明，糖尿病（DM）是患阿尔茨海默病（AD）的最强风险因素之一。然而，DM为何会加速AD病理过程仍不清楚。在25岁以上的食蟹猴中，其大脑中可自发且持续观察到老年斑（SPs），32岁及以上的食蟹猴会出现神经纤维缠结。在实验室饲养的猴子中，偶尔会观察到肥胖，且肥胖常导致2型糖尿病的发生。在本研究中，我们对患有2型糖尿病的食蟹猴脑组织进行了组织病理学和生化分析，以阐明DM与AD病理之间的关系。在此，我们提供证据表明，DM在未经过任何基因操作的非人灵长类动物体内加速了Aβ病理过程。在受DM影响的猴子大脑中，即使在20岁以下的猴子中，额叶和颞叶皮质也观察到了SPs。对大脑的生化分析表明，受DM影响的猴子大脑中GM1神经节苷脂结合Aβ（GAβ）——大脑中Aβ纤维形成的内源性种子——的量明显升高。此外，成年DM猴子大脑中Rab GTPases的水平也显著增加，几乎与老年猴子的水平相同。在受DM影响的猴子中还观察到神经元内扩大的内体积累，这表明内吞紊乱加剧可能是DM导致Aβ病理加速的原因。
