A novel trivalent cation chelator Feralex dissociates binding of aluminum and iron associated with hyperphosphorylated tau of Alzheimer's disease.
Aluminum (Al(III)) and iron (Fe(III)) are reported to accumulate in neurofibrillary tangles of the Alzheimer's disease (AD) brain. In these lesions Al (III) and Fe (III) bind with hyperphosphorylated tau (PHFtau), the major constituent of the lesions, and induce its aggregation. It is thought that inhibition and dissociation of such Al (III)/Fe (III) binding associated with PHFtau could slow or halt the tau-related neurofibrillary degeneration in patients with AD. A study, using a previously developed in vitro system in which Al (III) and Fe (III) interact with PHFtau on AD brain sections and on immunoblot membranes showed that the potent Al (III)/Fe (III) chelator desferrioxamine elicited Al (III) chelation when subjected to autoclave heating. Here, the ability of a recently developed chemical chelator Feralex-G to remove PHFtau-bound Al (III)/Fe (III), using reaction conditions at 37 degrees C, was examined and compared with that of desferrioxamine. Chelation of Fe(III) was achieved by both compounds with no discernible difference in their chelating ability. In contrast, in the present system, the two chelators gave a different Al (III) chelation response. When incubated at 37 degrees C, desferrioxamine failed to attain notable Al (III) chelation, while Feralex-G displayed efficient Al (III) chelation. Thus, when considering competitive Al (III) removal from brain PHFtau, Feralex-G is a stronger chelator for Al(III) than desferrioxamine. The efficient Al (III) chelation attainable by Feralex-G adds weight to its potential clinical usefulness as a medicine in the aluminum/iron chelation therapy for patients with AD.
Shin
Ryong-Woon
RW
Department of Neurological Science, Tohoku University School of Medicine, 2-1 Seiryo-machi, Sendai 980-8575, Japan.
Kruck
Theo P A
TP
Murayama
Harunobu
H
Kitamoto
Tetsuyuki
T
D000535:Aluminum / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002614:Chelating Agents / Q000494:pharmacology*; D003676:Deferoxamine / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D007501:Iron / Q000378:metabolism*; D009005:Monosaccharides / Q000494:pharmacology*; D010766:Phosphorylation; D011728:Pyridones / Q000494:pharmacology*; D016875:tau Proteins / Q000378:metabolism*
D002614:Chelating Agents; D009005:Monosaccharides; D011728:Pyridones; C447640:feralex; D016875:tau Proteins; D000535:Aluminum; D007501:Iron; D003676:Deferoxamine