Injection of bradykinin or cyclosporine A to hippocampus induces Alzheimer-like phosphorylation of Tau and abnormal behavior in rats / 中华医学杂志(英文版)

<p><b>OBJECTIVE</b>To reconstitute an Alzheimer's disease model by administering bradykinin (BK) or cyclosporine A (CSA) to the rat hippocampus.</p><p><b>METHODS</b>BK or CSA was administered to the rat hippocampus using a stereotaxic apparatus. The behavior of the rats was observed with an electronic attack jump platform. The phosphorylation of Tau protein was examined through immunohistochemical assay.</p><p><b>RESULTS</b>Behavior studies showed that an obvious disturbance in learning and memory was seen in BK injected rats.No obvious dysfunction was observed in CSA injected rats. The results obtained by immunohistochemical assay indicated that the staining of M4, 12E8, paired helical filament-1 (PHF-1) and calcium/calmodulin-dependent protein kinase II (CaMKII) was stronger, and that of Tau-1 was weaker in BK injected rats compared with the control group. We also found that the binding of M4 and PHF-1 but not 12E8 to Tau was significantly increased in CSA injected rats. As for BK injection, binding of Tau-1 to Tau was decreased after CSA injection.</p><p><b>CONCLUSION</b>To our knowledge, this is the first data showing in vivo that the activation of CaMKII induces both Alzheimer-like Tau phosphorylation and behavioral disturbances.</p>

Injection of bradykinin or/and cyclosporine A to hippocampus induces Alzheimer-like phosphorylation of tau and abnormal behavior in rats / 中国病理生理杂志

Bradykinin (BK) is a calcium/calmodulin dependent protein kinase Ⅱ (CaMKⅡ) specific activator, and Cyclosporin A (CSA) is reported to suppress protein phosphotase (PP)-2B activity. In vitro studies have shown that CaMKⅡ and PP-2B play an important role in Alzheimer-like phosphorylation of microtube-associated protein tau. To reconstitute an animal model based on the imbalance of protein kinase (s) and protein phosphatase (s) seen in Alzheimer brain, we injected BK and/or CSA into rat hippocampus. The results from behavioral study showed that an obvious disturbance in learning and memory was seen with BK or BK plus CSA injected rats. Moreover, the behavior abnormality appeared earlier in aged rats than young adults of the same kind after the injection. On the other hand, no obvious dysfunction in living and behavior was observed with CSA alone injected rats. The results obtained by immunohistochemical assay indicated that the staining for M4\, 12E8\, PHF-1 and CaMKⅡ was stronger, and for Tau-1 was weaker in BK injected rats compared with Control group. It was also found that the binding of M4 and PHF-1 but not 12E8 to tau was significantly increased in CSA injected rats. As the same as BK injection, binding of Tau-1 to tau was decreased after CSA injection. The immunostaining for 12E8\,PHF-1 and CaMKⅡ was increased, whereas for Tau-1\, M4\, and GSK-3 was decreased after combination injection of BK and CSA. In addition, the staining of PP-2B decreased in all the three models. To our knowledge, this is the first data shown in vivo that the activation of CaMKⅡ induces both Alzheimer-like tau phosphorylation and behavioral disturbance.

Calcium/calmodulin-dependent protein kinase Ⅱ and its biologic function / 中国病理生理杂志

Ca 2+/calmodulin-dependent protein kinase Ⅱ (CaMKⅡ) is a member of a family of Ca 2+/calmodulin-regulated protein kinases which also includes Ca 2+/calmodulin-dependent protein kinases Ⅰ and Ⅲ, myosin light chain kinases and phosphorylase kinase. Unlike the other members of this family, CaMKⅡ is multifunctional protein kinase and distributes in a variety of tissues. It is especially abundant in neuronal system. In hippocampus, CaMKⅡ is about 2% of the total protein. Studies have shown that CaMKⅡ plays an important role in a variety of biological processes, such as regulation of gene transcription, synthesis of neurotransmitter, phosphorylation of cytoskeletonal protein, hippocampal learning and memory formation.

Injection of bradykinin to hippocampus induces Alzheimer-like phosphorylation of tau and abnormal behavior in rat / 中华神经科杂志

Objective To reconstitute an animal model based on the imbalance of protein kinase(s) and protein phosphatase(s) seen in Alzheimer brain. Methods The injection of bradykinin (BK) into hipocampus was performed, and their behaviors were observed by electronic attack-jump experiment and phosphorylation of tau using immunohistochemical assay. Results The results of behavior studying showed that an obvious disturbance in learning and memory was seen in BK injected rats. The results obtained by immunohistochemical assay indicated that the staining for M4?12E8?PHF-1 and CaMK-Ⅱ was stronger, and for tau-1 was weaker in BK injected rats as compared with the control group. The BK injected rats showed obvious deficit in behavior [mistakes made by model and control rats during electronic attack-jump experiment:8.3?2.5 and 6.9?3.1, P