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Abstract：
The key to the prevention and treatment of Alzheimer\'s disease (AD) is to be able to predict and diagnose AD at the preclinical or early stage, but the lack of a preclinical model of AD is the critical factor that causes this problem to remain unresolved.
We assessed 18 monkeys in vivo evaluation of pro-inflammatory cytokines and AD pathological biomarkers (n = 9 / type 2 diabetic mellitus (T2DM) group, age 20, fasting plasma glucose (FPG) ≥ 100 mg/dL, and n = 9 / negative control (NC) group, age 17, FPG < 100 mg/dL). Levels of pro-inflammatory cytokines and AD pathological biomarkers was measured by ELISA and Simoa Technology, respectively. 9 monkeys evaluated ex vivo for AD-like pathology (n = 6 / T2DM group, age 22.17, FPG ≥ 126 mg/dL, and n = 3 / NC group, age 14.67, FPG < 100 mg/dL). To evaluate the pathological features of AD in the brains of T2DM monkeys, we assessed the levels of Aβ, phospho-tau, and neuroinflammation using immunohistochemistry, which further confirmed the deposition of Aβ plaques by Bielschowsky\'s silver, Congo red, and Thioflavin S staining. Synaptic damage and neurodegeneration were assessed by immunofluorescence.
We found not only increased levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) in peripheral blood (PB) and brain of T2DM monkeys but also changes in PB of AD pathological biomarkers such as decreased β-amyloid (Aβ) 42 and Aβ40 levels. Most notably, we observed AD-like pathological features in the brain of T2DM monkeys, including Aβ plaque deposition, p-tau from neuropil thread to pre-neurofibrillary tangles (NFTs), and even the appearance of extracellular NFT. Microglia were activated from a resting state to an amoeboid. Astrocytes showed marked hypertrophy and an increased number of cell bodies and protrusions. Finally, we observed impairment of the postsynaptic membrane but no neurodegeneration or neuronal death.
Overall, T2DM monkeys showed elevated levels of peripheral and intracerebral inflammation, positive AD biomarkers in body fluids, and developing AD-like pathology in the brain, including Aβ and tau pathology, glial cell activation, and partial synaptic damage, but no neuronal degeneration or death as compared to the healthy normal group. Hereby, we consider the T2DM monkeys with elevation of the peripheral pro-inflammatory factors and positive AD biomarkers can be potentially regarded as a preclinical AD model.
We assessed 18 monkeys in vivo evaluation of pro-inflammatory cytokines and AD pathological biomarkers (n = 9 / type 2 diabetic mellitus (T2DM) group, age 20, fasting plasma glucose (FPG) ≥ 100 mg/dL, and n = 9 / negative control (NC) group, age 17, FPG < 100 mg/dL). Levels of pro-inflammatory cytokines and AD pathological biomarkers was measured by ELISA and Simoa Technology, respectively. 9 monkeys evaluated ex vivo for AD-like pathology (n = 6 / T2DM group, age 22.17, FPG ≥ 126 mg/dL, and n = 3 / NC group, age 14.67, FPG < 100 mg/dL). To evaluate the pathological features of AD in the brains of T2DM monkeys, we assessed the levels of Aβ, phospho-tau, and neuroinflammation using immunohistochemistry, which further confirmed the deposition of Aβ plaques by Bielschowsky\'s silver, Congo red, and Thioflavin S staining. Synaptic damage and neurodegeneration were assessed by immunofluorescence.
We found not only increased levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) in peripheral blood (PB) and brain of T2DM monkeys but also changes in PB of AD pathological biomarkers such as decreased β-amyloid (Aβ) 42 and Aβ40 levels. Most notably, we observed AD-like pathological features in the brain of T2DM monkeys, including Aβ plaque deposition, p-tau from neuropil thread to pre-neurofibrillary tangles (NFTs), and even the appearance of extracellular NFT. Microglia were activated from a resting state to an amoeboid. Astrocytes showed marked hypertrophy and an increased number of cell bodies and protrusions. Finally, we observed impairment of the postsynaptic membrane but no neurodegeneration or neuronal death.
Overall, T2DM monkeys showed elevated levels of peripheral and intracerebral inflammation, positive AD biomarkers in body fluids, and developing AD-like pathology in the brain, including Aβ and tau pathology, glial cell activation, and partial synaptic damage, but no neuronal degeneration or death as compared to the healthy normal group. Hereby, we consider the T2DM monkeys with elevation of the peripheral pro-inflammatory factors and positive AD biomarkers can be potentially regarded as a preclinical AD model.
摘要：
背景：预防和治疗阿尔茨海默病（AD）的关键是能够在临床前或早期预测和诊断AD，但是缺乏AD的临床前模型是导致该问题仍未解决的关键因素.
方法：我们评估了18只猴子体内促炎细胞因子和AD病理生物标志物的评估（n=9/2型糖尿病（T2DM）组，20岁，空腹血糖（FPG）≥100mg/dL，n=9/阴性对照（NC）组，17岁，FPG<100mg/dL)。通过ELISA和Simoa技术检测促炎细胞因子和AD病理生物标志物的水平，分别。9只猴子离体评估了AD样病理（n=6/T2DM组，年龄22.17岁，FPG≥126mg/dL，n=3/NC组，年龄14.67岁，FPG<100mg/dL)。评价T2DM猴脑内AD的病理特征,我们评估了Aβ的水平，磷酸-tau，和神经炎症使用免疫组织化学，这进一步证实了Bielschowsky的银沉积Aβ斑块，刚果红,和硫黄素S染色。通过免疫荧光评估突触损伤和神经变性。
结果：我们不仅发现T2DM猴外周血（PB）和脑中促炎细胞因子如肿瘤坏死因子-α（TNF-α）的水平升高，而且AD病理生物标志物的PB也发生变化，如β-淀粉样蛋白（Aβ）42和Aβ40水平降低。最值得注意的是,我们观察到T2DM猴脑内AD样病理特征,包括Aβ斑块沉积，从神经纤维线到神经原纤维缠结（NFT）的p-tau，甚至细胞外NFT的出现。小胶质细胞从静息状态被激活为变形虫。星形胶质细胞显示出明显的肥大和细胞体和突起的数量增加。最后,我们观察到突触后膜受损，但没有神经变性或神经元死亡。
结论：总体而言，T2DM猴表现出外周和脑内炎症水平升高，体液中AD生物标志物阳性，并在大脑中发展出类似AD的病理，包括Aβ和tau病理学，胶质细胞活化，和部分突触损伤，但与健康正常组相比，没有神经元变性或死亡。特此,我们认为伴有外周促炎因子升高和AD生物标志物阳性的T2DM猴可能被视为临床前AD模型.
方法：我们评估了18只猴子体内促炎细胞因子和AD病理生物标志物的评估（n=9/2型糖尿病（T2DM）组，20岁，空腹血糖（FPG）≥100mg/dL，n=9/阴性对照（NC）组，17岁，FPG<100mg/dL)。通过ELISA和Simoa技术检测促炎细胞因子和AD病理生物标志物的水平，分别。9只猴子离体评估了AD样病理（n=6/T2DM组，年龄22.17岁，FPG≥126mg/dL，n=3/NC组，年龄14.67岁，FPG<100mg/dL)。评价T2DM猴脑内AD的病理特征,我们评估了Aβ的水平，磷酸-tau，和神经炎症使用免疫组织化学，这进一步证实了Bielschowsky的银沉积Aβ斑块，刚果红,和硫黄素S染色。通过免疫荧光评估突触损伤和神经变性。
结果：我们不仅发现T2DM猴外周血（PB）和脑中促炎细胞因子如肿瘤坏死因子-α（TNF-α）的水平升高，而且AD病理生物标志物的PB也发生变化，如β-淀粉样蛋白（Aβ）42和Aβ40水平降低。最值得注意的是,我们观察到T2DM猴脑内AD样病理特征,包括Aβ斑块沉积，从神经纤维线到神经原纤维缠结（NFT）的p-tau，甚至细胞外NFT的出现。小胶质细胞从静息状态被激活为变形虫。星形胶质细胞显示出明显的肥大和细胞体和突起的数量增加。最后,我们观察到突触后膜受损，但没有神经变性或神经元死亡。
结论：总体而言，T2DM猴表现出外周和脑内炎症水平升高，体液中AD生物标志物阳性，并在大脑中发展出类似AD的病理，包括Aβ和tau病理学，胶质细胞活化，和部分突触损伤，但与健康正常组相比，没有神经元变性或死亡。特此,我们认为伴有外周促炎因子升高和AD生物标志物阳性的T2DM猴可能被视为临床前AD模型.
