Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
PLoS One. 2011;6(8):e24032. doi: 10.1371/journal.pone.0024032. Epub 2011 Aug 26.
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: F(2,26) = 12.62; p = 0.0002; SMIT2: F(2,26) = 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.
肌醇立体异构体，即肌醇和鲨肌醇，已知能进入大脑，并在口服后显著升高。由于从外围的主动转运，脑内肌醇水平沿浓度梯度升高。有两种钠/肌醇转运体（SMIT1、SMIT2）可能负责调节脑内肌醇水平。本研究的目的是确定衰老和阿尔茨海默病（AD）样淀粉样蛋白病理对转运体表达的影响，比较区域表达，并分析肌醇转运体的底物要求。QPCR 用于检测 TgCRND8 小鼠（一种淀粉样蛋白病理模型）的大脑皮质、海马和小脑中两种转运体的表达，与非转基因同窝仔鼠进行比较。此外，我们还利用基于细胞的竞争摄取测定法，检查了主动转运所需的肌醇结构特征。疾病病理没有改变皮质或海马中的转运体表达（p＞0.005），仅在小脑中观察到衰老的微小影响（SMIT1：F（2，26）=12.62；p=0.0002；SMIT2：F（2，26）=8.71；p=0.0015）。总的来说，大脑 SMIT1 水平高于 SMIT2，但观察到了区域差异。对于 SMIT1，在 4 个月和 6 个月时，小脑 SMIT1 水平明显高于皮质和海马水平（p＜0.05）。对于 SMIT2，在所有三个年龄阶段，皮质和小脑 SMIT2 水平均明显高于海马水平（p＜0.05），在 4 个月和 6 个月时，小脑 SMIT2 水平也明显高于皮质水平（p＜0.05）。肌醇转运体水平作为年龄的函数稳定表达，并且在 TgCRND8 小鼠中，疾病病理不会改变其表达。鉴于目前鲨肌醇正在进行 AD 治疗的临床试验，无论疾病病理如何，肌醇转运体的稳定表达都是一个重要发现。
