Defective gallium-transferrin binding in Alzheimer disease and Down syndrome: possible mechanism for accumulation of aluminium in brain

Farrar, Gillian; Blair, J. Anthony; Altmann, Paul; Welch, S.G.; Wychrij, O; Ghose, Bhabani Charan; Lejeune, J; Corbett, John A.; Prasher, V. P.

doi:10.1016/0140-6736(90)90868-6

Cited by 115 publications

(31 citation statements)

References 25 publications

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“…This latter observation further suggests that aluminum is accessing the same cellular regulatory routes as iron. Recent studies on the 67Ga binding activity of the plasma Tf obtained from Alzheimer and Down syndrome patients have also suggested that altered Tf-ion binding activity may play a role in differential metal ion access to the brains of these patients (26).…”

Section: Methodsmentioning

confidence: 99%

Aluminum access to the brain: a role for transferrin and its receptor.

Roskams

Connor

1990

Proc. Natl. Acad. Sci. U.S.A.

207

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The toxicity of aluminum in plant and animal cell biology is well established, although poorly understood. Several recent studies have identified aluminum as a potential, although highly controversial, contributory factor in the pathology of Alzheimer disease, amyotrophic lateral sclerosis, and dialysis dementia. For example, aluminum has been found in high concentrations in senile plaques and neurofibrillary tangles, which occur in the brains of subjects with Alzheimer disease. However, a mechanism for the entry of aluminum (Al3+) into the cells of the central nervous system (CNS) has yet to be found. Here we describe a possible route of entry for aluminum into the cells of the CNS via the same high-affmnity receptor-ligand system that has been postulated for iron (Fe3 ) delivery to neurons and glial cells. These results suggest that aluminum is able to gain access to the central nervous system under normal physiological conditions. Furthermore, these data suggest that the interaction between transferrin and its receptor may function as a general metal ion regulatory system in the CNS, extending beyond its postulated role in iron regulation.

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Section: Methodsmentioning

confidence: 99%

Aluminum access to the brain: a role for transferrin and its receptor.

Roskams

Connor

1990

Proc. Natl. Acad. Sci. U.S.A.

207

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“…Farrar et al (105) used HPLC and gel electrophoresis to study the binding of radioactive gallium (which they presumed to be analogous to aluminum) to transferrin. Binding was lower in people with either AD or Down's syndrome than in normal subjects.…”

Section: Kinetics Ofaluminum Uptake By Cellsmentioning

confidence: 99%

The biological speciation and toxicokinetics of aluminum.

DeVoto

Yokel

1994

Environ Health Perspect

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This review discusses recent literature on the chemical and physiological factors that influence the absorption, distribution, and excretion of aluminum in mammals, with particular regard to gastrointestinal absorption and speciation in plasma. Humans encounter aluminum, a ubiquitous yet highly insoluble element in most forms, in foods, drinking water, and pharmaceuticals. Exposure also occurs by inhalation of dust and aerosols, particularly in occupational settings. Absorption from the gut depends largely on pH and the presence of complexing ligands, particularly carboxylic acids, with which the metal can form absorbable neutral aluminum species. Uremic animals and humans experience higher than normal body burdens of aluminum despite increased urinary clearance of the metal. In plasma, 80-90% of aluminum binds to transferrin, an iron-transport protein for which receptors exist in many tissue. The remaining fraction of plasma aluminum takes the form of small-molecule hydroxy species and small complexes with carboxylic acids, phosphate, and, to a much lesser degree, amino acids. Most of these species have not been observed in vivo but are predicted from equilibrium models derived from potentiometric methods and NMR investigations. These models predict that the major small-molecule aluminum species under plasma conditions are charged and hence unavailable for uptake into tissues.

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“…In principal, SDAT patients with normal levels of total cir culating and bone aluminium might have excessive amounts of aluminium crossing the blood-brain barrier by virtue of increased levels of unbound versus transfer rin-bound aluminium. Evidence exists to support this hypothesis in that gallium, which behaves very similarly to aluminium biochemically, is less well bound to plasma transferrin in AD and Down syndrome [17], Down syn drome patients being relevant to studies in AD patho physiology in that they have an estimated 45% risk of ADtype dementia by their mid-40s [18]. Extrapolating this evidence to aluminium, it has been suggested that in AD there is an increased proportion of circulating aluminium which is unbound to transferrin, given the same total con centrations of aluminium in plasma as normal individu als.…”

Section: Discussionmentioning

confidence: 70%

Bone Aluminium Content in Alzheimers Disease

O’Mahony

Denton

Templar

et al. 1995

Dement Geriatr Cogn Disord

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The possible association between aluminium and Alzheimer’s disease is still contentious. If aluminium neurotoxicity is implicated in the pathophysiology of Alzheimer''s disease, it may result either from excessive aluminium exposure or increased brain aluminium uptake. In a pilot study to test the former hypothesis, trabecular bone aluminium content, which reflects long-term aluminium exposure, was evaluated in 7 patients with a clinical diagnosis of senile dementia of the Alzheimer type (SDAT; mean age 80.8 ± 3.35 years) and 19 non-demented age-matched controls (mean age 79.6 ± 6.09 years). Trabecular bone was obtained from post-traumatic femoral neck fracture specimens taken from patients during femoral head prosthesis surgery. Bone aluminium content was expressed quantitatively by atomic absorption spectrometry and qualitatively by the acid solochrome azurine histological staining technique. Quantitative analysis showed a lower aluminium content in the SDAT (11.9 ± 4.04 µg/g dry bone) versus the non-demented group (18.2 ± 7.37 µg/g), which was significant at the 95% but not at the 99% confidence limit. Aluminium deposition from qualitative histological analysis was not detectable in either group. These results do not support a hypothesis of excessive aluminium absorption and tissue accumulation in Alzheimer''s disease.

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Defective gallium-transferrin binding in Alzheimer disease and Down syndrome: possible mechanism for accumulation of aluminium in brain

Cited by 115 publications

References 25 publications

Aluminum access to the brain: a role for transferrin and its receptor.

Aluminum access to the brain: a role for transferrin and its receptor.

The biological speciation and toxicokinetics of aluminum.

Bone Aluminium Content in Alzheimers Disease

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