Solubilization of beta-amyloid-(1-42)-peptide: reversing the beta-sheet conformation induced by aluminum with silicates.

Abstract

Plaques are one of the two lesions found in the brain of patients with Alzheimer disease. Using a synthetic peptide corresponding to rat ,B-amyloid-(1-42) (j3A4), circular dichroism (CD) analyses were performed to examine the effect of Na4SiO4 on the conformational state produced by Al3+. A previous study on fragments of neuronal proteins involved in tangle formation had shown a conformational transition from a 8-pleated sheet to a soluble random coil upon addition of Na4SiO4. In the present study, CD measurements showed that the f3-pleated sheet conformation of f3A4 induced by Al3+ was reversed to the random coil soluble form by the addition of Na4SiO4. The tight binding of Al3+ provides the mechanism for this transition. These results provide insight into the role of aluminum in the Alzheimer diseased brain and suggests the investigation of the use of silicates as a therapeutic agent.Alzheimer disease (AD) will probably become the predominant social-medical-economic problem in the next century. An estimated 4 million Americans now have the disease, and this number is expected to grow to >10 million within the next decade (1). The cause of AD is not known, and treatments are only mildly effective at slowing the degeneration process (2). The signs of AD, obtained upon autopsy of the diseased brain, reveal two phenomena: amyloid plaques and neurofibrillary tangles (3). The amyloid plaques are composed primarily of a 39-to 42-amino acid fragment (13A4) from the amyloid precursor protein (4). Tangles contain abnormally phosphorylated tau protein that combine to form paired helical filaments within the neuron (5). In addition to the protein components of plaques and tangles, some researchers have detected aluminum (6, 7) and aluminosilicates (8) in these lesions, although the evidence for their presence is apparently controversial (9).Aluminum is known to have toxic effects (10) on many organisms, including man. Aluminum is an associated risk factor in amyotrophic lateral sclerosis, Parkinsonismdementia of Guam, and AD (11,12).Aluminum is the third most abundant element in the earth's crust, found primarily as insoluble aluminosilicates and oxides. However, it is soluble as aluminum hydroxide and aluminum hydrates at acidic pH values (13). This has become a biologic concern as the world's water supplies become more acidic due to acid rain. For (18,19). The formation of 13-pleated sheets could be reversed by the addition of silicates (20).The current paper is a study of the ,3A4 peptide (residues 1-42 of the ,B-amyloid precursor protein), whose prominent role in the progression of AD has been frequently stressed and has been reviewed extensively (21-23). Several structural studies on 13A4 or its fragments have been reported (24)(25)(26)(27)(28). CD studies illustrated the requirements for 13-sheet filament formation (29). Solid-state Fourier-transform infrared spectroscopy showed that the secondary structure consisted of a 13-turn flanked by two strands of antiparallel 1-pleated sheet (30). In aqueous tri...

Can the Controversy of the Role of Aluminum in Alzheimer's Disease Be Resolved? What Are the Suggested Approaches to This Controversy and Methodological Issues to Be Considered?

“…It has been shown that physiological concentrations of Al alter the conformation of Ab , abolishing the a -helical conformation and promoting the formation of the b -turn and random coil structures (Exley et al, 1993), and it has been suggested that this is the mechanism by which Al blocks the calcium channels formed by Ab . Subsequent to this finding of an interaction between Al and Ab , several papers have confirmed an influence of Al on the conformation and subsequent aggregation of this peptide (Mantyh et al, 1993;Kawahara et al, 1994;Chong & Suh, 1995;Fasman et al, 1995;Vyas & Duffy, 1995). However, in each of these publications the effects of Al have only been significant at high concentrations of >100 µmol Al/L (and sometimes, high concentrations of peptide) and the resultant amyloidAl complexes had little organized structure.…”

Oral silicon supplementation: an effective therapy for preventing oral aluminum absorption and retention in mammals

“…Although highly controversial, the potential effects of Al or Si concentrations in drinking water on the risk of developing AD remain an issue of notable interest. The use of Si/silicates as a possible therapeutic agent for preventing Al accumulation has been suggested by various investigators 38,61,92–96 . Whether dietary Si supplementation could be of therapeutic value to prevent chronic Al accumulation in the brain, and hence, a potential therapy for AD seems worthy of further investigation.…”

Prevention and Treatment of Aluminum Toxicity Including Chelation Therapy: Status and Research Needs

“…Addition of Al to b -amyloid solutions caused the amyloid to adopt a potentially neurotoxic b -sheet conformation. Orthosilicate reversed this conformation, suggesting the possible use of silicates as therapeutic agents for AD (Fasman et al, 1995). Further studies are needed to verify that these changes are due to Si and could occur in vivo.…”