Sodium/myo-Inositol Transporters: Substrate Transport Requirements and Regional Brain Expression in the TgCRND8 Mouse Model of Amyloid Pathology

Abstract

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.

Tilapia (Oreochromis mossambicus) brain cells respond to hyperosmotic challenge by inducingmyo-inositol biosynthesis

“…Moreover, no known reported literature has cited exogenous pathways as highly inducible under salinity challenge in the brain of fishes. In contrast, several studies on mammalian systems highlight the exogenous cotransporter pathways as a primary mechanism for intracellular myo-inositol accumulation (Fenili et al, 2011;Ibsen and Strange, 1996;Inoue et al, 1996) in the brain. It is possible that mammalian systems have diverged in their preferred mechanism for myo-inositol accumulation in the cell.…”

Activation of osmolyte pathways in inflammatory myopathy and Duchenne muscular dystrophy points to osmoregulation as a contributing pathogenic mechanism

“…The constitutive SMIT levels in the brain 17 were found moderately increased in the hippocampus of aged mice; 38 however, severity of tissue damage was not related to SMIT expression in TgCRND8, a mouse model of Alzheimer's disease-like amyloid pathology. 39 …”

The “Other” Inositols and Their Phosphates: Synthesis, Biology, and Medicine (with Recent Advances inmyo‐Inositol Chemistry)

“…[66] The expression levels of the sodium/myo-inositol transporters do not differ between healthy individuals and those with Alzheimer's disease. [67] A phase 2 clinical trial of scyllo-inositol established a twice daily dose of 250mg as being safe, but the sample size was too small to establish efficacy. [68] scyllo-Inositol inhibits the aggregation of Aβ in Alzheimer's disease and also inhibits the neuronal aggregation of α-synuclein, a pathological hallmark of Parkinson's disease.…”