Age-related changes in levels of tyrosine kinase B receptor and fibroblast growth factor receptor 2 in the rat inferior colliculus: implications for neural senescence.
Age-related changes in levels of tyrosine kinase B receptor and fibroblast growth factor receptor 2 in the rat inferior colliculus: implications for neural senescence.
复制标题
大鼠下丘酪氨酸激酶 B 受体和成纤维细胞生长因子受体 2 水平与年龄相关的变化：对神经衰老的影响。
DOI：
10.1016/s0306-4522(01)00022-7
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发表时间：
2001
期刊：
影响因子：
3.3
通讯作者：
Helfert,RH
中科院分区：
文献类型：
--
作者：
Sato,T;Wilson,TS;Hughes,LF;Konrad,HR;Nakayama,M;Helfert,RH
已知脑源性神经营养因子和成纤维细胞生长因子 2 及其各自的结合位点酪氨酸激酶 B 受体和成纤维细胞生长因子受体 2 可调节神经突生长和抗氧化酶活性。多项研究表明，下丘中含有脑源性神经营养因子和成纤维细胞生长因子。我们实验室之前的工作揭示了老年 Fischer-344 大鼠下丘的树突和突触损失，以及脂质过氧化的同时增加，可能与抗氧化酶活性的降低有关。为了确定下丘中发生的与年龄相关的突触和树突损失的潜在因果机制，本研究试图确定下丘酪氨酸激酶 B 受体和成纤维细胞生长因子受体 2 表达的水平是否随年龄而改变。对3月龄F344大鼠的下丘、海马和小脑进行免疫细胞化学研究，研究酪氨酸激酶B受体和成纤维细胞生长因子受体2的全长和截短亚型的分布。后两个脑区作为阳性对照。对于所有三种抗原，免疫标记主要位于下丘所有分区的体细胞和近端树突，以及海马的齿状回和阿蒙角。在小脑中，浦肯野细胞的体细胞和树突也被免疫标记。使用蛋白质印迹分析发现，18 个月大和 25 个月大的大鼠中全长形式的酪氨酸激酶 B 受体水平显着降低（分别相对于 3 个月大的大鼠约 20% 和 30%）。在两个较大年龄组中，截断形式的下丘和海马水平也略有下降（~7%）。相比之下，与 3 个月大的孩子相比，两个较大年龄组的下丘和海马中成纤维细胞生长因子受体 2 的水平升高了约 35%。小脑酪氨酸激酶B受体和成纤维细胞生长因子受体2水平的变化虽然与各年龄组中下丘和海马的变化相似，但在本研究中并未达到统计学意义。这些发现表明，与年龄相关的酪氨酸激酶 B 受体水平降低可能是老年动物下丘退行性变化的一个致病因素，包括线粒体损伤和树突退化。观察到的成纤维细胞生长因子受体2水平的增加可能是对氧化应激增加的补偿。鉴于老年动物下丘和海马体发生损伤，成纤维细胞生长因子受体 2 反应的有效性值得怀疑。然而，如果成纤维细胞生长因子受体 2 不增加，这种缺陷可能会恶化。
Brain-derived neurotrophic factor and fibroblast growth factor 2, and their respective binding sites, tyrosine kinase B receptor and fibroblast growth factor receptor 2, are known to regulate neurite outgrowth and antioxidant enzyme activity. Several studies suggest that brain-derived neurotrophic factor and fibroblast growth factor are contained in the inferior colliculus. Previous work in our laboratories revealed dendritic and synaptic losses in the inferior colliculus of aged Fischer-344 rats, along with coincident increases in lipid peroxidation possibly linked to a decrease in activity of antioxidant enzymes. In an effort to identify potential causal mechanisms underlying age-related synaptic and dendritic losses that occur in the inferior colliculus, the present study attempted to determine if inferior colliculus levels of tyrosine kinase B receptor and fibroblast growth factor receptor 2 expression are altered with age. Immunocytochemistry was performed in the inferior colliculus, hippocampus and cerebellum of 3-month-old F344 rats to study distributions of the full-length and truncated isoforms of tyrosine kinase B receptor, and fibroblast growth factor receptor 2. The latter two brain regions served as positive controls. For all three antigens, immunolabeling was localized primarily in somata and proximal dendrites in all subdivisions of the inferior colliculus, and in the dentate gyrus and Ammon's horn of the hippocampus. In the cerebellum, the somata and dendrites of the Purkinje cells were also immunolabeled. A significant reduction in levels of the full-length form of tyrosine kinase B receptor in 18- and 25-month-old rats (respectively, ∼20% and 30% relative to 3-month-olds) was revealed using western blot analyses. Inferior colliculus and hippocampal levels of the truncated form were modestly decreased (∼7%) as well in the two older age groups. In contrast, levels of fibroblast growth factor receptor 2 in the inferior colliculus and hippocampus were elevated by approximately 35% in the two older age groups when compared to 3-month-olds. Changes in cerebellar levels of tyrosine kinase B receptor and fibroblast growth factor receptor 2, while similar to those in the inferior colliculus and hippocampus among the age groups, did not achieve statistical significance in this study. These findings give rise to the possibility that age-related reductions in tyrosine kinase B receptor levels could be a causal factor in the degenerative changes observed in the inferior colliculus of aged animals, including mitochondrial damage and dendritic regression. The observed increases in fibroblast growth factor receptor 2 levels may be compensatory to the increased oxidative stress. The effectiveness of the fibroblast growth factor receptor 2 response is questionable given the damage that occurs in the inferior colliculus and hippocampus of aged animals. However, the deficits could worsen in the absence of an increase in fibroblast growth factor receptor 2.