Region-Specific Vulnerability to Oxidative Stress, Neuroinflammation, and Tau Hyperphosphorylation in Experimental Diabetes Mellitus Mice
Region-Specific Vulnerability to Oxidative Stress, Neuroinflammation, and Tau Hyperphosphorylation in Experimental Diabetes Mellitus Mice
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DOI：
10.3233/jad-150820
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发表时间：
2016-01-01
影响因子：
4
通讯作者：
Hattori, Nobutaka
中科院分区：
文献类型：
--
作者：
Elahi, Montasir;Hasan, Zafrul;Hattori, Nobutaka
最近的流行病学证据表明，糖尿病（DM）是阿尔茨海默病（AD）的危险因素。AD的病理标志之一是过度磷酸化的tau蛋白，其形成神经元缠结。氧化应激和炎症通路的激活是与DM和AD相关的特征。然而，AD相关神经变性的脑区域特异性，主要发生在海马，而小脑相对不受影响，尚未得到澄清。因此，我们使用实验性DM小鼠（由腹腔注射链脲佐菌素[STZ]引起）来确定这些神经退行性变相关机制是否与区域特异性选择性脆弱性或tau蛋白磷酸化相关。在用STZ处理后，评价老年（14至18个月大）非转基因（NTg）和过表达野生型人tau的转基因小鼠（Tg 601小鼠）的海马、中脑和小脑。STZ注射增加活性氧，脂质过氧化标记物，如4-羟基壬烯醛和丙二醛在海马，但不是在中脑或小脑。STZ治疗还增加了海马中Iba-1阳性和CD 68阳性小胶质细胞、星形胶质细胞的数量以及IL-1 β、IL-6、IL-10和IL-18水平，但在中脑或小脑中没有。Tau蛋白过度磷酸化在海马中也增强，但在中脑或小脑中没有。当在Tg 601和NTg小鼠之间比较STZ的作用时，Tg 601小鼠中的小胶质细胞增殖和IL-6和磷酸化tau的升高更高。这些结果表明，STZ治疗小鼠的神经炎症和氧化应激与tau蛋白过度磷酸化有关，这可能有助于人类AD的选择性神经变性。
Recent epidemiological evidence suggests that diabetes mellitus (DM) is a risk factor for Alzheimer's disease (AD). One of the pathological hallmarks of AD is hyperphosphorylated tau protein, which forms neurofibrillary tangles. Oxidative stress and the activation of inflammatory pathways are features that are associated with both DM and AD. However, the brain region specificity of AD-related neurodegeneration, which mainly occurs in the hippocampus while the cerebellum is relatively unaffected, has not yet been clarified. Therefore, we used experimental DM mice (caused by an intraperitoneal injection of streptozotocin [STZ]) to determine whether these neurodegeneration-associated mechanisms were associated with region-specific selective vulnerability or tau phosphorylation. The hippocampus, midbrain, and cerebellum of aged (14 to 18 months old) non-transgenic (NTg) and transgenic mice overexpressing wild-type human tau (Tg601 mice) were evaluated after a treatment with STZ. The STZ injection increased reactive oxygen species, lipid peroxidation markers such as 4-hydroxynonenal and malondialdehyde in the hippocampus, but not in the midbrain or cerebellum. The STZ treatment also increased the number of Iba-1-positive and CD68-positive microglial cells, astrocytes, and IL-1 beta, IL-6, IL-10, and IL-18 levels in the hippocampus, but not in the midbrain or cerebellum. Tau hyperphosphorylation was also enhanced in the hippocampus, but not in the midbrain or cerebellum. When the effects of STZ were compared between Tg601 and NTg mice, microglial proliferation and elevations in IL-6 and phosphorylated tau were higher in Tg601 mice. These results suggest that neuroinflammation and oxidative stress in STZ-treated mice are associated with tau hyperphosphorylation, which may contribute to selective neurodegeneration in human AD.