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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: 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.
PLoS ONE 01/2011; 6(8):e24032. · 4.09 Impact Factor
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ABSTRACT: Amyloid-beta (Abeta) aggregation and amyloid formation are key pathological features of Alzheimer's disease, and are considered to be two of the major contributing factors to neurodegeneration and dementia. Identification of small molecule inhibitors that are orally available, have low toxicity and high central nervous system bioavailability is one approach to the potential development of a disease-modifying treatment for Alzheimer's disease. We have previously identified inositol stereoisomers as exhibiting stereospecific inhibition of Abeta aggregation and toxicity in vitro and in vivo. We report here the effects of inosose versus inositol stereoisomers on Abeta fibrillogenesis as determined using CD and fluorescence spectroscopy and negative-stain electron microscopy. The inososes differ from inositols by the oxidation of one of the hydroxyl groups to a ketone. These molecules help in the further elucidation of the structure-activity relationships of inositol-Abeta interactions and identify both allo-inositol and epi-2-inosose as in vitro inhibitors of Abeta aggregation.
FEBS Journal 05/2008; 275(8):1663-74. · 3.79 Impact Factor
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ABSTRACT: Amyloid-β (Aβ) aggregation and amyloid formation are key pathological features of Alzheimer’s disease, and are considered to be two of the major contributing factors to neurodegeneration and dementia. Identification of small molecule inhibitors that are orally available, have low toxicity and high central nervous system bioavailability is one approach to the potential development of a disease-modifying treatment for Alzheimer’s disease. We have previously identified inositol stereoisomers as exhibiting stereospecific inhibition of Aβ aggregation and toxicity in vitro and in vivo. We report here the effects of inosose versus inositol stereoisomers on Aβ fibrillogenesis as determined using CD and fluorescence spectroscopy and negative-stain electron microscopy. The inososes differ from inositols by the oxidation of one of the hydroxyl groups to a ketone. These molecules help in the further elucidation of the structure–activity relationships of inositol–Aβ interactions and identify both allo-inositol and epi-2-inosose as in vitro inhibitors of Aβ aggregation.
FEBS Journal 03/2008; 275(8):1663 - 1674. · 3.79 Impact Factor
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ABSTRACT: Inositol is a simple polyol with eight naturally occurring stereoisomers. myo-Inositol, D-chiro- and epi-inositol have been examined as potential therapeutic agents for various diseases, with favorable results, but treatment with scyllo-inositol has not been previously investigated. Our laboratory has shown that scyllo-inositol inhibits cognitive deficits in TgCRND8 mice and significantly ameliorates disease pathology, suggesting it might be effective in treating Alzheimer's disease (AD). In this paper, we show that scyllo-inositol has a sustained ability to treat animals at advanced stages of AD-like pathology. Significant decreases in insoluble Abeta40, Abeta42, and plaque accumulation were observed in the brains of treated versus untreated TgCRND8 mice. The growth of plaques of all sizes was inhibited by scyllo-inositol administration. To demonstrate that the scyllo-inositol effects were within the CNS, gas chromatography/mass spectrometry was used to examine myo- and scyllo-inositol concentrations after oral administration. Further, we examined how closely scyllo- and myo-inositol are inter-regulated in the CNS and whether scyllo-inositol, if elevated within the CNS, would incorporate into phosphatidylinositol lipids. Cerebral spinal fluid levels of scyllo-inositol increased after scyllo-inositol treatment but not myo-inositol treatment. scyllo-Inositol treatment also caused increased levels of scyllo-inositol in the brain. We further show that scyllo-inositol, even at elevated levels, does not incorporate into the phosphatidylinositol family of lipids. These combined results demonstrate that scyllo-inositol accumulates within the CNS up to tenfold endogenous levels and does not interfere with phosphatidylinositol lipid production.
Journal of Molecular Medicine 07/2007; 85(6):603-11. · 4.67 Impact Factor
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ABSTRACT: Alzheimer's disease (AD) is a debilitating disease that affects many people. In order to reduce the number of people diagnosed with this disease, drug strategies need to be implemented that target early steps in disease pathogenesis. Elevated cholesterol levels and presence of the apolipoprotein E eta4 allele increase AD risk. How these two factors may contribute to AD pathogenesis and some therapeutic strategies for alleviating AD risk will be discussed.
Current Drug Targets - CNS & Neurological Disorders 11/2005; 4(5):553-67.
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ABSTRACT: The utility of vaccine strategies to treat neurodegenerative diseases such as Alzheimer's disease (AD) may still hold promise. Both active and passive immunization strategies reduced AD-like pathology and restored cognitive deficits in transgenic mice. These results were initially met with considerable optimism; however, phase IIa clinical trials were halted because of a small but significant occurrence of meningoencephalitis. Knowledge gained from studies on amyloid-beta peptide (A beta) immunotherapy will allow optimization of new-generation vaccines, targeting highly specific epitopes while reducing undesired side effects. In harnessing and steering the immune system, an effective response can be generated against A beta. If this proves successful, A beta vaccination could provide the first definitive treatment for AD.
Proceedings of the National Academy of Sciences 11/2004; 101 Suppl 2:14657-62. · 9.68 Impact Factor
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ABSTRACT: The culture of organotypic slices for the purposes of tracking dynamic cellular events within the same live cell at high resolution, as a function of development in vitro has not been previously reported. The present study was undertaken to define the conditions most suitable for both the in vitro organotypic development of Purkinje neurons in cerebellar slices of neonatal mice, and the repeated visualization of nuclear signals within such cells. Slices of cerebella were maintained on 25 mm diameter, collagen-coated Anodisc membranes, placed in six-well plates and raised to the air-medium interface by use of glass fibre filter supports. This system permits cultures to be repeatedly observed both by phase contrast microscopy and, upon biolistic transfection, by laser confocal microscopy using 40x, 60x, and 100x water-immersion objectives, at high resolution. Upon co-transfection with two plasmids, differentiation of the same transfected Purkinje neurons was followed across in vitro development for periods of up to 10 days. Despite the relative thickness of the slice culture, even small, punctate, nuclear signals, were detectable. The results show that Purkinje neurons in cerebellar slices explanted from postnatal day 2 mice, developed cytotypically, although some were ectopically located. In contrast, Purkinje neurons in slices from postnatal day 6 cerebella developed in an organotypic manner. It is concluded that this culture system serves as an ideal tool for applications in experimental biology where high resolution tracking of cellular signals, over extended time periods, is of interest.
Brain Research Protocols 06/2003; 11(2):101-10. · 1.82 Impact Factor
