Detection of increased scyllo-inositol in brain with magnetic resonance spectroscopy after dietary supplementation in Alzheimer's disease mouse models

Abstract

There is evidence that inositol isomers may help protect against formation of toxic fibrils of Abeta fragments in Alzheimer's disease mouse models. Scyllo-inositol is one of the more promising inositol isomers for the potential treatment of Alzheimer's disease (AD) and can be detected using MRS in human subjects. In this manuscript we demonstrate using MRS, in two different mouse models of AD (APP x PS1 and APP x PS1 x tau), that we could detect increased scyllo-inositol in the hippocampus and frontal cortex in mice fed water supplemented with 16.5 mg/L of scyllo-inositol equivalent to about 3.3 mg/kg/day. We used both brain extracts using solution MRS as well as intact brain tissue using high resolution magic angle spinning (HRMAS) to ensure that any membrane-associated scyllo-inositol would be detected. By brain extracts we detected a 3.0 fold increase in scyllo-inositol in the scyllo-fed AD mice compared to normal diet (p < 0.001). Using HRMAS we detected a 2.2-2.4-fold increase in scyllo-inositol (p < 0.001). Scyllo-inositol treatment was associated with an increase in glutamine in hippocampus. The concentrations of scyllo-inositol were higher in the hippocampus than in the frontal cortex. Mice have a smaller concentration of scyllo-inositol than humans (ca. 100 microM vs. 500 microM in humans). Given the ease with which scyllo-inositol can be measured in human MRS data with high signal to noise ratios, these data suggest that MRS will prove useful for evaluation of inositol treatment trials in AD subjects.

Figure 1

A) Figure showing the region from which tissue was taken for both frontal cortical studies using the APP×PS1 and triple trasngene mice. B) Picture from a mouse brain atlas at the levels of the hippocampus (subiculum) showing the approximate region (blue) from which the tissue punches were taken. Shown on the right is the corresponding slice from a six month old mouse showing immunohistochemical stains for amyloid ß protein (Aβ_1-42) in the hippocampus (shown in the figure on the right). The region from which the punch was taken is a region showing intense Aβ accumulation.

Figure 2

Four HRMAS spectra from the hippocampus of two triple transgene mice with and two without dietary scyllo-inositol supplementation. There was little overlap in the scyllo-inositol values between the two groups of mice (p<0.001).

Figure 3

Bar graph showing the increase in scyllo-inositol in the scyllo-fed versus regular diet animals normalized to creatine. Values shown are molar ratios. The data come from brain extracts of frontal cortex in APP×PS1 mice and frontal cortex and hippocampus using HRMAS in APP×PS1×tau mice. The scyllo-inositol increases by about a factor of 2-3 in the two groups.