Scyllo-inositol may limit or reverse Alzheimer disease because it appears to inhibit the uptake of myo-inositol in the brain and thus stops the overproduction of D-myo-inositol-1,4,5-triphosphate, a compound which plays a critical role in regulating calcium in the cytoplasm of nerve cells. If there is too much D-myo-inositol-1,4,5-triphosphate, calcium levels should rise. The enzyme which cleaves off the beta amyloid protein may be activated by high intracellular calcium levels. Thus, high levels of D-myo-inositol-1,4,5-triphosphate would likely lead to the aggregation of beta amyloid proteins.

The high levels of myo-inositol in the pre-dementia phase of people with Down syndrome, and the high levels of myo-inositol monophosphatase (which converts myo-inositol monophosphates into myo-inositol) in post-mortem Alzheimer disease brains implicate myo-inositol in these two forms of dementia. High levels of myo-inositol also correlate with insulin-resistant diabetes, which may help explain the link between diabetes and Alzheimer disease as well as why insulin-like nerve...  Read more

Scyllo-inositol may limit or reverse Alzheimer disease because it appears to inhibit the uptake of myo-inositol in the brain and thus stops the overproduction of D-myo-inositol-1,4,5-triphosphate, a compound which plays a critical role in regulating calcium in the cytoplasm of nerve cells. If there is too much D-myo-inositol-1,4,5-triphosphate, calcium levels should rise. The enzyme which cleaves off the beta amyloid protein may be activated by high intracellular calcium levels. Thus, high levels of D-myo-inositol-1,4,5-triphosphate would likely lead to the aggregation of beta amyloid proteins.

The high levels of myo-inositol in the pre-dementia phase of people with Down syndrome, and the high levels of myo-inositol monophosphatase (which converts myo-inositol monophosphates into myo-inositol) in post-mortem Alzheimer disease brains implicate myo-inositol in these two forms of dementia. High levels of myo-inositol also correlate with insulin-resistant diabetes, which may help explain the link between diabetes and Alzheimer disease as well as why insulin-like nerve growth factors also show promise against the disease. Myo-inositol monophosphate is produced from glucose-6-phosphate with the phosphate being added by ATP (when glucose enters into a cell it is converted into glucose-6-phosphate; the more glucose that enters into a cell the more glucose-6-phosphate is produced). ATP also probably plays an important role in the conversion process from there: myo-inositol/myo-inositol monophosphate, phosphatidyl-myo-inositol-4,5-biphosphate, myo-inositol-1,4,5-triphosphate. It is possible, however, that phosphates from other sources (phosphoric acids, aluminum phosphates, and biphosphates such as Fosamax) and phosphate analogs (such as aluminum fluoride and sodium fluoride) accelerate the creation of myo-inositol triphosphate and thus the onset of Alzheimer disease.

Scyllo-inositol may not be as easily taken up into lipids as myo-inositol. "Scyllo-inositol biphosphate" may not be as easy to cleave off from lipids as myo-inositol biphosphates, or "scyllo-inositol triphosphate" may not work with calcium receptors as effectively as myo-inositol triphosphates. The end result should be lower levels of calcium and fewer beta amyloid proteins being generated. The slowing down in the processing of beta amyloid proteins may allow for some or all of those proteins to be moved out of the nerve cells or otherwise eliminated.

View all comments by Lane Simonian

This is the latest in a series of papers evaluating the efficacy of specific inositol stereoisomers to ameliorate phenotypes of Aβ pathology. It extends investigation of effects of Aβ oligomer-containing 7PA2 cell culture media on synaptic function into behavioral tasks in a rat infusion model. The observed effects appear to be due to blocking oligomers binding to neuronal membranes, which would directly affect toxicity while also improving the chances for clearance of small oligomers.

Importantly, the investigators measure and report dose-dependent levels of AZD-103 in CSF of rats who have had either 30, 100, or 300 mg/kg/day of AZD-103 added to their drinking water. The concentrations attained are 20-50 microM, well above the single-digit microM required to neutralize the effects of the infused 7PA2 cell media. This direct demonstration of AZD-103 bioavailability is often a difficult hurdle to overcome for putative therapeutics. Of course, the pharmacodynamics and pharmacokinetics remain to be worked out, since a continuous dosing in patients is unlikely.

The results...  Read more

This is the latest in a series of papers evaluating the efficacy of specific inositol stereoisomers to ameliorate phenotypes of Aβ pathology. It extends investigation of effects of Aβ oligomer-containing 7PA2 cell culture media on synaptic function into behavioral tasks in a rat infusion model. The observed effects appear to be due to blocking oligomers binding to neuronal membranes, which would directly affect toxicity while also improving the chances for clearance of small oligomers.

Importantly, the investigators measure and report dose-dependent levels of AZD-103 in CSF of rats who have had either 30, 100, or 300 mg/kg/day of AZD-103 added to their drinking water. The concentrations attained are 20-50 microM, well above the single-digit microM required to neutralize the effects of the infused 7PA2 cell media. This direct demonstration of AZD-103 bioavailability is often a difficult hurdle to overcome for putative therapeutics. Of course, the pharmacodynamics and pharmacokinetics remain to be worked out, since a continuous dosing in patients is unlikely.

The results raise a number of questions worth considering:

1. The experiments on AZD-103 competition with antibodies to different epitopes are hard to interpret because the apparent affinity of AZD-103 for oligomers (~100 nM) is relatively low compared to that of most antibodies (~1 nM). In addition, as a consequence of the proximity effect of having multiple antibody epitopes on the oligomers and the high density of antibody on the beads, the antibodies might easily out-compete the compound for binding to oligomers.

2. Does AZD-103-coupled epoxy-Sepharose remove oligomer activity from 7PA2 culture media (controlled with chiro-inositol-Sepharose)? The Western blots (Figs 3d and Suppl. 1E) are very light and not very convincing. There may be subpopulations of small-n oligomers that bind tightly but are minimally involved in activity against LTP.

3. Is the continued presence of AZD-103 with 7PA2 cell culture media required for neutralization? Since its affinity is relatively low, implying exchangeability, can AZD-103 be removed by gel filtration or dialysis? If it can be removed, and activity against LTP is still blocked, this would suggest a “conversion” activity, which would amplify the utility of the compound. The observed decreases in A11 anti-oligomer reactivity could be due not to disassembly of oligomers, but to a conformational rearrangement. Previously published studies (McLaurin et al., 2000) indicate this for synthetic Aβ(1-42).

4. There is always an issue about the extrapolation of synthetic peptide experiments to biologically produced material, hence the 7PA2 cell culture media experiments. The reverse question is also important in terms of being able to have sufficient quantities of reproducible preparations that can be characterized more completely than cell culture media. Do similar experiments performed with purified synthetic oligomers of Aβ1-42, both in the hippocampal slices and the rat infusion model, show activity, and is AZD-103 as effective at similar concentrations of Aβ and in the same size fractions (SEC) of oligomers?

Looking to the future, it is even more important to ask the question of whether the cell culture-derived material is representative of the soluble oligomers found in humans, including controls (some nondemented people have significant Aβ), MCI, and early and late AD. Oligomers produced by a transfected overexpressing cell line may differ in important ways from the assemblies found in human AD brain or even Tg mouse brain. How do the sizes and concentrations of cell culture Aβ oligomers compare with Tg mouse and human brain and CSF material?

The investigators now have the systems (hippocampal slices, rat ICV infusion) to potentially, after dialysis, disentangle the effects of other substances in tissue extracts. While purification may be difficult, it should be possible to differentiate the effects of the oligomers in soluble Tg mouse or human brain and CSF extracts from those of contaminants by judicious dose control and IP of Aβ and AZD-103 neutralization.

View all comments by Harry LeVine III