Johnson G V, Watson A L, Lartius R, Uemura E, Jope R S
Department of Psychiatry and Behavioral Neurobiology, University of Alabama, Birmingham 35294-0017.
Neurotoxicology. 1992 Summer;13(2):463-74.
Administration of 0.3% aluminum in drinking water elevated serum aluminum concentrations 8-fold in rats. Further, chronic treatment with aluminum for 2-3 mon, in both developing and adult rats, significantly decreased the levels of MAP-2 in brain, as determined by quantitative immunoblot analysis. Aluminum treatment also decreased the level of brain spectrin, but only in the hippocampus of adult rats. These were selective effects, since the levels of tubulin, tau and the three proteins of the neurofilament triplet were unaltered. In the aluminum-treated adult rats MAP-2 levels were significantly decreased in the hippocampus and brainstem to 71% and 56% of control values, respectively. In developing rats, MAP-2 levels were significantly decreased in the cortex and brainstem (65 and 64% of control values, respectively) but not in the hippocampus. In support of these findings, immunohistochemical examination revealed that the intensity of hippocampal MAP-2 immunoreactivity was significantly decreased to 88% of control values with aluminum treatment in adult rats. To determine a possible mechanism by which MAP-2 levels are reduced, the effect of aluminum on calpain-induced proteolysis of MAP-2 was examined in vitro. At the aluminum concentrations tested, there was no apparent effect on calpain-induced proteolysis of MAP-2. In the developing rats, aluminum administration significantly increased the hippocampal cyclic AMP concentration, as reported previously in adult aluminum-treated rats, and decreased the inositol 1,4,5-trisphosphate concentration. These results demonstrate that chronic oral aluminum administration to rats selectively decreases the levels of MAP-2 in specific brain regions independent of calpain proteolysis. This decrease may be associated with increased cyclic AMP and protein phosphorylation, and the impairment of cognition previously observed in this model of aluminum intoxication.
在饮用水中添加0.3%的铝可使大鼠血清铝浓度升高8倍。此外，对发育期和成年大鼠进行为期2 - 3个月的铝慢性治疗后，通过定量免疫印迹分析测定发现，大脑中微管相关蛋白2（MAP-2）的水平显著降低。铝治疗还降低了脑血影蛋白水平，但仅在成年大鼠的海马体中出现这种情况。这些都是选择性作用，因为微管蛋白、tau蛋白和神经丝三联体的三种蛋白水平未发生改变。在经铝处理的成年大鼠中，海马体和脑干中的MAP-2水平分别显著降低至对照值的71%和56%。在发育期大鼠中，皮质和脑干中的MAP-2水平显著降低（分别为对照值的65%和64%），但海马体中未降低。为支持这些发现，免疫组织化学检查显示，成年大鼠经铝处理后，海马体MAP-2免疫反应强度显著降低至对照值的88%。为确定MAP-2水平降低的可能机制，在体外研究了铝对钙蛋白酶诱导的MAP-2蛋白水解的影响。在所测试的铝浓度下，对钙蛋白酶诱导的MAP-2蛋白水解没有明显影响。在发育期大鼠中，铝的给药显著增加了海马体环磷酸腺苷（cAMP）浓度，正如先前在成年铝处理大鼠中所报道的那样，并降低了肌醇1,4,5-三磷酸浓度。这些结果表明，对大鼠进行慢性口服铝给药可选择性降低特定脑区中MAP-2的水平，且与钙蛋白酶蛋白水解无关。这种降低可能与cAMP增加和蛋白磷酸化有关，以及先前在这种铝中毒模型中观察到的认知障碍有关。
