The silicon link between aluminium and Alzheimer’s disease
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Journal of Alzheimer’s Disease 10 (2006) 39–42 39 IOS Press Commentary - The silicon link between aluminium and Alzheimer’s disease - Andrei C. Miu; Program of Cognitive Neuroscience, Department of Psychology, Babes¸-Bolyai University, 37 Republicii,
Cluj-Napoca, CJ 400015, Romania [Tel./Fax: +40 264 590967; E-mail: AndreiMiu@psychology.ro]
The silicon link between aluminium and Alzheimer's disease (PDF Download Available). Available from: https://www.researchgate.net/publication/299055075_The_silicon_link_between_aluminium_and_Alheimer%27s_disease [accessed Jun 11 2018].
Christopher Exley and colleagues report in this issue of JAD  the results of a clinical study showing that drinking silicic acid (Si(OH)4)-rich mineral water for ﬁve days signiﬁcantly reduces the urinary excretion of aluminium, but not iron in Alzheimer disease (AD) patients. The authors argue that the long-term dietary supplementation of Si(OH)4might qualify as a non-invasive therapy for reducing the body burden of aluminium in AD. This study opens a new chapter of the investigations of J. Derek Birchall’s hypothesis of a silicon link between aluminium and AD, for it offers a direct demonstration of the efﬁcacy of dietary silica supplementation in increasing the excretion of aluminium in AD. But what can we expect in terms of therapeutic effects from stimulating the aluminium urinary excretion in AD? We will brieﬂy discuss here the context and implications of this study.
The systematic interest for the utilization of silicon in medicine can be traced back to the late nineteenth century, when the emulation of physiologists for research on this element led Luis Pasteur to predict that silicon reserved important therapeutic applications in many human diseases. However, the recognition of silicon as an essential trace element came only in 1972 when two reports showed that dietary silicon deprivation in chicks and rats was associated with retarded growth and bone deformities [6,28]. Subsequent research has established that silicon is indeed important for the calciﬁcation of bone and cartilage, and it may be thus involved in disorders characterized by an imbalance between bone formation and resorption (e.g., osteoporosis), joint disorders (e.g., osteoarthritis), and even heart disease and aging (for review see ).
In contrast to the rather straightforward demonstrations of the roles of silicon in bone and connective tissue homeostasis, the link between silicon and neuropathology and particularly AD was put forward via the aluminium hypothesis in AD. Taking account of the high chemical afﬁnity of silicon for aluminium, and the typical inverse relation between the concentrations of aluminium and silicon in water supplies, the British chemist J.D. Birchall suggested that silicon might mediate the effect of aluminium from drinking water on AD incidence [2,3]. This suggestion was partly based on an earlier ﬁnding reported by Birchall, Exley and coworkers that Si(OH)4in water protected salmon against fatal ionoregulatory, osmoregulatory and respiratory dysfunctions causedbytoxic aluminium binding to the gill epithelium [4,14].
Following Birchall’s suggestion, several epidemiological studies reviewed in  (see also ) indicated that the protective effect of silicon from drinking water against AD was only modest. Nonetheless, in spite of this apparent rebuttal of Birchall’s hypothesis, the silicon link between aluminium and AD continued to be supported on other lines of research. For instance, silicon, more speciﬁcally as silica oligomers , reduced by several folds the gastrointestinal absorption of aluminium in humans  and increased its urinary excretion , as originally suggested ; high serum silicon was shown to be associated with low serum aluminium concentrations in dyalisis patients ; the aluminium-induced beta-pleated conformation of the amyloid-β1−42 was reversed to a random coil conformation by addition of silicate in solution [17,18] (see also the United States Patent 5523295  for Fasman’s “method for treating and preventing AD”!); and, ﬁnally, the brain aluminium content was 24 to 126% higher in various regions of the brain of rats with high aluminium and low silicon dietcomparedto those withhighaluminium and silicon diet .These studies supported the idea that a candidate mechanism for the biological essentiality of silicon might be its ability to control the biological availability of toxic aluminium .
Nonetheless, in recent years, the silicon-aluminium-ADlink has shared the fate of the aluminium hypothesis in AD and it has drawn little attention from neuroscientists. The study of Exley et al.  makes a challenging comeback of this hypothesis straight in the clinical ﬁeld of AD.
The study of Exley et al. is clearly complementary to that of Bellia et al.  who investigated the urinary excretion of 26 aluminium in healthy volunteers given silicon hydroxide [Si(OH)4], although the relevance of the study now published in JAD is widen by the investigation of AD patients. Bellia et al.  observed that the administration of increasing doses of Si(OH)4was associated with a peak followed by decline of aluminium urinary excretion, a fact which they interpreted as proof of depletion of aluminium from body stores. Based on the low serum but high urine concentration of silicon in their participants, the same authors inferred that the interaction of silicon with aluminium to form an excretable species probably took place in the kidney lumen.
With the complementarity between the two studies in mind, it might seem odd why Exley et al. chose to align their investigation with a previous two-year prospective, single-blind clinical trial in which intramuscular administration of desferrioxamine, a metal chelator with high afﬁnities for iron and aluminium, copper and zinc, was shown to decrease the rate of decline of daily living skills in patients with probable AD . However encouraging at the moment when it was published, that study has not been followed by a double-blind placebo-controlled multicenter trial, although such a follow-up was promptly called . The discouragement on the clinical application of desferrioxamine in AD has been justiﬁed by the poor absorption and rapid degradation of this chelator in the gastrointestinal tract, which implies carefully monitored, long-term therapy, its hydrophilicity that made its ability to cross the blood-brain barrier debatable, and last but not least its neurological side effects (for review and refs. see ). Moreover, the study of Crapper McLachlan et al.  has not excluded the possibility that the removal of iron, instead of aluminium, might have supported the therapeutic effect of desferrioxamine (see [22,29]). Consequently, although this study has been widely cited as “a fourth major line of evidence” for the aluminium hypothesis in AD, the apparent success of desferrioxamine in delaying (but not arresting!) the behavioral decline in AD has not signiﬁcantly changed the status quo of the aluminium-AD theory, still characterized to date as an open question  or a hypothesis not convincinglydemonstrated .
Anyway, Exleyet al. place their present research in the framework of chelation therapy in AD and they refer to the study of Crapper McLachlan et al.  in order to argue that purging the body burden of aluminium and retaining it at low levels in humans is an alternative approach to proving the aluminium-AD link, which, in their view, might even bring more promising results than animal models and epidemiology (for other perspectives see [19,25]). We argue that there is a difference between the assumptions of chelation therapy in AD and the approach put forward by Exley et al. While chelation therapy studies target the depletion of aluminium and other metals in aging and AD (for review see ), that is, conditions in which aluminium has presumably accumulated in pathogenetic concentrations in the brain, the intervention of Exley et al. is clearly ﬁtter as a prophylactic means of preventing the accumulation of aluminium in the brain, to be initiated from young ages. Only in this context can we appreciate the merits of the present intervention, for it is inexpensive (i.e., it relies on dietary silica supplementation from readily available sources like Si(OH)4mineral water, but also tea from silicon-rich plants like the horse-tail plant, and grapes and wine; see ), non-invasive (i.e., it does not even have to interfere with the usual diet), free of side-effects (i.e., more than half of the ingested silicon is excreted in the ﬁrst 8 hours  and the aluminium whose urinary excretion is stimulated has no physiological role) and associated with minimal discomfort from participants. To our understanding, the intervention of Exley et al. might best be used in AD-free individuals, in which this harmless Si(OH)4 dietary supplementation might serve to minimize an increased body burden of aluminium on the long-term and eventually prevent the pathogenic accumulation ofthis metal in the brain.
Nonetheless, the present study tested Si(OH)4dietary supplementation on aluminium urinary excretion in AD patients. While these original results show that Si(OH)4increases the aluminium urinary excretion in AD patients and healthy volunteers alike, follow-up studies should further adapt this intervention in healthy volunteers and strongly recommended it as prophylaxis against aluminium accumulation in the brain, acknowledged to date as one of the risk factors in AD. Would this intervention be as efﬁcient in depleting brain aluminium in diagnosed AD? We cannot be certain. We know that silicon crosses the blood-brain barrierand enters cerebral circulation because aluminosilicates have been found in senile plaques . We are also sure that there are multiple carrier-mediated transport systems across the blood-brain barrier, which allow aluminium to enter and leave cerebral circulation (for review see ). However, we do not know if the product of the interaction of silicon and aluminium in the brain would also be able to cross the blood-brain barrier and leave cerebral circulation (e.g., see ). As rightfully acknowledged in the present report and judiciously emphasized by Exley somewhere else , the formation of hydroxyaluminosilicates has not been demonstrated in vivo. Taking into account that an increased urinary excretion of aluminium following Si(OH)4has been attributed to a probable interaction of the two elements in the kidney , the urinary aluminium excretion reasonably indicates a reduced body burden of aluminium in healthy individuals for which there is no reason to expect aluminium accumulation in the brain. As long as we do not know more about the biochemical interaction of silicon and aluminium in vivo, and particularly in the brain, and about the mechanisms used by the product of this interaction for leaving the cerebral circulation, the interpretation of an increased urinary aluminium excretion after Si(OH)4supplementation in conditions involving aluminium accumulation in the brain is less straightforward.
In conclusion, the study of Exley et al. published in this issue of JAD extends previous investigations on healthy volunteers and shows that Si(OH)4dietary supplementation facilitates the urinary excretion of aluminium in AD patients, in whom there is considerable evidence of aluminium accumulation in the brain. Without the present evidence that the silicon-aluminium mechanism that works in healthy volunteers works the same in AD patients, it would have been difﬁcult to argue that the long-term dietary silica supplementation and its effects in preventing aluminium accumulation in the body and probably brain is relevant to AD prophylaxis. Therefore, the present study reduces an important degree of freedom that would have otherwise limited the possible clinical developments of the silicon-aluminium-AD hypothesis and it strengthens aforeseeable health recommendation of silica supplementation therapy as a long-term prophylaxis against AD. Such an intervention might allow us to easily control a risk factor involved in AD pathogenesis and it should equally draw the attention of individuals and health organizations.
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