Sodium/myo-Inositol transporters: substrate transport requirements and regional brain expression in the TgCRND8 mouse model of amyloid pathology.
Sodium/myo-Inositol transporters: substrate transport requirements and regional brain expression in the TgCRND8 mouse model of amyloid pathology.
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DOI：
10.1371/journal.pone.0024032
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
McLaurin J
中科院分区：
文献类型：
--
作者：
Fenili D;Weng YQ;Aubert I;Nitz M;McLaurin J
肌醇立体异构体，肌肌醇和鲨肌醇，已知进入大脑，并在口服给药后显著升高。脑肌醇水平的升高是由于从外周主动转运而跨越浓度梯度发生的。有两种钠/肌醇转运蛋白（SMIT 1，SMIT 2）可能负责调节脑肌醇水平。本研究的目的是确定衰老和阿尔茨海默病（AD）样淀粉样蛋白病理学对转运蛋白表达的影响，比较区域表达并分析肌醇转运蛋白的底物需求。使用QPCR检查TgCRND 8小鼠（淀粉样蛋白病理学的小鼠模型）的皮质、海马和小脑中两种转运蛋白的表达，并与非转基因同窝仔进行比较。此外，我们研究了肌醇的结构特征所需的主动运输，利用基于细胞的竞争性摄取测定。疾病病理学没有改变皮质或海马中转运蛋白的表达（p>0.005），在小脑中仅观察到最小的衰老影响（SMIT 1：F2，26 = 12.62; p = 0.0002; SMIT 2：F2，26 = 8.71; p = 0.0015）。 总体而言，大脑SMIT 1水平高于SMIT 2，但观察到区域差异。对于SMIT 1，在4和6个月时，小脑SMIT 1水平显著高于皮质和海马水平（p<0.05）。对于SMIT 2，在所有三个年龄，皮质和小脑SMIT 2水平均显著高于海马水平（p<0.05），并且在4月龄和6月龄，小脑SMIT 2水平也显著高于皮质水平（p<0.05）。肌醇转运蛋白水平作为年龄的函数稳定表达，并且在TgCRND 8小鼠中表达不随疾病病理改变。考虑到鲨肌醇目前正处于治疗AD的临床试验中，肌醇转运蛋白的稳定表达与疾病病理无关是一个重要的发现。
Inositol stereoisomers, myo- and scyllo-inositol, are known to enter the brain and are significantly elevated following oral administration. Elevations in brain inositol levels occur across a concentration gradient as a result of active transport from the periphery. There are two sodium/myo-inositol transporters (SMIT1, SMIT2) that may be responsible for regulating brain inositol levels. The goals of this study were to determine the effects of aging and Alzheimer's disease (AD)-like amyloid pathology on transporter expression, to compare regional expression and to analyze substrate requirements of the inositol transporters. QPCR was used to examine expression of the two transporters in the cortex, hippocampus and cerebellum of TgCRND8 mice, a mouse model of amyloid pathology, in comparison to non-transgenic littermates. In addition, we examined the structural features of inositol required for active transport, utilizing a cell-based competitive uptake assay. Disease pathology did not alter transporter expression in the cortex or hippocampus (p>0.005), with only minimal effects of aging observed in the cerebellum (SMIT1: F2,26 = 12.62; p = 0.0002; SMIT2: F2,26 = 8.71; p = 0.0015). Overall, brain SMIT1 levels were higher than SMIT2, however, regional differences were observed. For SMIT1, at 4 and 6 months cerebellar SMIT1 levels were significantly higher than cortical and hippocampal levels (p<0.05). For SMIT2, at all three ages both cortical and cerebellar SMIT2 levels were significantly higher than hippocampal levels (p<0.05) and at 4 and 6 months of age, cerebellar SMIT2 levels were also significantly higher than cortical levels (p<0.05). Inositol transporter levels are stably expressed as a function of age, and expression is unaltered with disease pathology in the TgCRND8 mouse. Given the fact that scyllo-inositol is currently in clinical trials for the treatment of AD, the stable expression of inositol transporters regardless of disease pathology is an important finding.
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影响因子：
4.7
作者：
Choi, Ji-Kyung;Carreras, Isabel;Dedeoglu, Alpaslan;Jenkins, Bruce G.
通讯作者：
Jenkins, Bruce G.
影响因子：
4.8
作者：
Ostlund, RE;Seemayer, R;Sherman, WR
通讯作者：
Sherman, WR
影响因子：
4.4
作者：
BERRY, GT;MALLEE, JJ;SPINNER, NB
通讯作者：
SPINNER, NB
影响因子：
5.5
作者：
Bissonnette, P;Coady, MJ;Lapointe, JY
通讯作者：
Lapointe, JY
影响因子：
3.5
作者：
Roll, P;Massacrier, A;Szepetowski, P
通讯作者：
Szepetowski, P