Organosilicon therapy in Alzheimer's disease?

I was immediately intrigued by the title of the paper by Friedman and colleagues [7]. A tumult of thoughts ensued as I fought for a basis for linking organosiloxanes with the treatment of neurodegenerative disease! Needless to say, I was surprised at the authors’ contention that organosiloxanes might be used therapeutically to prevent or dissolve metal-mediated deposits of brain amyloid though my surprise was tempered by knowledge of an earlier and similar suggestion by Fasman and colleagues that inorganic silicates might be used to the same end [6]. Friedman et al. have acknowledged Fasman et al. as the origin of their idea but were they mislead by the earlier publication? According to the abstract and conclusions Fasman et al. demonstrated that an aluminium-induced transition towards β-sheet conformers of Aβ42 could be reversed to random coil soluble forms of the peptide by the addition of sodium orthosilicate (Na4SiO4) and, crucially, that this effect was attributable to the tight binding of Al by SiO4− 4 . Unfortunately this conclusion was not supported by their experiments. What they did show was that in a non-aqueous medium of 2,2,2 trifluoroethanol (TFE) the addition of Al (dissolved in TFE) induced a conformational change in Aβ42 from predominantly α-helix/random coil to one which included a significant component ofβ-sheets. When an aqueous solution of Na4SiO4 was subsequently added to the mixture of Aβ42/Al/TFE a partial reversal of the β-sheet transition was achieved at a SiO4− 4 to Al ratio of 1.0. This effect may, as the authors suggested, have been due to the titration of Al out of Aβ42 though none of the required control experiments were carried out to confirm this. For example, we do not know if the observed effect was due to (i) the addition of water (from the addition of aqueous Na4SiO4) to the Aβ42/Al/TFE mixture; (ii) the increase in pH which would occur when aqueous Na4SiO4 (pH > 11.0!!) was added to the mixture; (iii) the rapid formation of metal-greedy polysilicic acids which would have occurred when a 138 mM Na 4SiO4 was added to an acidic Aβ42/Al/TFE mixture or (iv) SiO4− 4 binding of Al at ‘mixture’ pH > 10. Even if the appropriate control experiments had demonstrated that the reversal of the β-sheet transition was due to SiO4− 4 titrating Al out of Aβ42 what would be the physiological significance of such since under the conditions which could occur in brain fluid the only biologically available form of Si is silicic acid (Si(OH)4) [2]. My interpretation of Friedman et al., at least in its original form, is that the authors were mislead to the extent that they have looked to extend Fasman’s earlier studies by appending a notional SiO4− 4 functionality to a lipid soluble carrier to improve the accessibility of such a group to a target site in the brain. Once in situ in sufficiently high concentrations the organosilicate would titrate aluminium, and other metals, out of precipitated deposits of Aβ42 and prevent any further metal-amyloid induced neuronal damage [9]. Friedman et al. have shown that both aluminium and iron were able to promote the formation of βsheet conformers of Aβ42 and, indeed, that the addi-