Altered levels and distribution of IGF-II/M6P receptor and lysosomal enzymes in mutant APP and APP+PS1 transgenic mouse brains
Altered levels and distribution of IGF-II/M6P receptor and lysosomal enzymes in mutant APP and APP+PS1 transgenic mouse brains
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DOI：
10.1016/j.neurobiolaging.2007.05.004
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发表时间：
2009-01-01
影响因子：
4.2
通讯作者：
Kar, S.
中科院分区：
文献类型：
--
作者：
Amritraj, A.;Hawkes, C.;Kar, S.
胰岛素样生长因子-II/6-磷酸甘露糖 (IGF-II/M6P) 受体参与溶酶体酶从跨高尔基体网络或细胞表面到溶酶体的运输。在阿尔茨海默病（AD）大脑中，脆弱神经元群中溶酶体系统的显着上调与代谢功能的改变相关。为了确定携带不同家族性 AD 突变的转基因小鼠大脑中 IGF-II/M6P 受体和溶酶体酶是否发生改变，我们测量了过表达突变早老素 1 (PS1; PS1(M1461+1.286V))、淀粉样前体蛋白 (APP; APP(KM670/671NL+V717F)) 或 APP + PS1 (APPKM(670/671NL+V717F) + PS1(M1461+1.286V)) 转基因 我们的结果显示，APP 和 APP + PS1 的海马和额叶皮质中 IGF-II/M6P 受体和溶酶体酶的水平和表达增加，但与野生型对照小鼠相比，PS1 转基因小鼠大脑中没有这种情况。 APP + PS1 中的变化比 APP 单一转基因小鼠更显着。此外。 APP 和 APP + PS1 转基因小鼠的海马和皮质区域中所有含有 β-淀粉样蛋白的神经炎斑块对两种溶酶体酶均呈免疫阳性，而只有一部分斑块显示出 IGF-II/M6P 受体免疫反应性。这些结果表明，位于脆弱区域的神经元中 IGF-II/M6P 受体和溶酶体酶的上调反映了内体-溶酶体系统功能的改变，这可能与在 APP 和 APP + PS1 转基因小鼠大脑中观察到的细胞内和/或细胞外 Aβ 沉积物增加有关。 (C) 2007 年，爱思唯尔公司出版。
The insulin-like growth factor-II/mannose-6-phosphate (IGF-II/M6P) receptor participates in the trafficking of lysosomal enezymes from the trans-Golgi network or the cell surface to lysosomes. In Alzheimer's disease (AD) brains, marked up-regulation of the lysosomal system in vulnerable neuronal populations has been correlated with altered metabolic functions. To establish whether IGF-II/M6P receptors and lysosomal enzymes are altered in the brain of transgenic mice harboring different familial AD mutations, we measured the levels and distribution of the receptor and lysosomal enzymes cathepsins B and D in select brain regions of transgenic mice overexpressing either mutant presenilin 1 (PS1; PS1(M1461+1.286V)), amyloid precursor protein (APP; APP(KM670/671NL+V717F)) or APP + PS1 (APPKM(670/671NL+V717F) + PS1(M1461+1.286V)) transgenes Our results revealed that levels and expression of the IGF-II/M6P receptor and lysosomal enzymes are increased in the hippocampus and frontal cortex of APP and APP + PS1, but not in PS1, transgenic mouse brains compared with wild-type controls. The changes were more prominent in APP + PS1 than in APP single transgenic mice. Additionally. all beta-amyloid-containing neuritic plaques in the hippocampal and cortical regions of APP and APP + PS1 transgenic mice were immunopositive for both lysosomal enzymes, whereas only, a subset of the plaques displayed IGF-II/M6P receptor immunoreactivity. These results suggest that up-regulation of the IGF-II/M6P receptor and lysosomal enzymes in neurons located in vulnerable regions reflects an altered functioning of the endosomal-lysosomal system which may be associated with the increased intracellular and/or extracellular A beta deposits observed in APP and APP + PS1 transgenic mouse brains. (C) 2007 Published by Elsevier Inc.