Region-Specific Vulnerability to Oxidative Stress, Neuroinflammation, and Tau Hyperphosphorylation in Experimental Diabetes Mellitus Mice

被引:35
|
作者
Elahi, Montasir [1 ,2 ]
Hasan, Zafrul [1 ]
Motoi, Yumiko [1 ,2 ,3 ]
Matsumoto, Shin-Ei [2 ,3 ]
Ishiguro, Koichi [3 ]
Hattori, Nobutaka [2 ,3 ]
机构
[1] Juntendo Univ Grad Med, Sportol Ctr, Tokyo, Japan
[2] Juntendo Univ Grad Med, Dept Diag Prevent & Treatment Dementia, Tokyo, Japan
[3] Juntendo Univ Grad Med, Dept Neurol, Tokyo, Japan
关键词
Alzheimer's disease; cytokines; diabetes mellitus; microglia; neuroinflammation; oxidative stress; tauopathy; ALZHEIMERS-DISEASE; LIPID-PEROXIDATION; IN-VIVO; MICROGLIAL ACTIVATION; INSULIN-RESISTANCE; DEFECTIVE INSULIN; NEUROPATHIC PAIN; MOUSE MODEL; HUMAN BRAIN; AGED MICE;
D O I
10.3233/JAD-150820
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:1209 / 1224
页数:16
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