A recent study has correlated the pathogenesis of various dementies with a relative insufficiency of magnesium (Mg) in the brain (Glick, 1990). Such insufficiency may be attributable to low intake or retention of Mg; high intake of a neurotoxic metal, such as aluminum (A1), which inhibits activity of Mg-requiring enzymes; or impaired transport of Mg and/or enhanced transport of the neurotoxic metal into brain tissue. Alzheimer's disease (AD) appears to involve a defective transport process, characterized by both an abnormally high incorporation of A1 and an abnormally low incorporation of Mg into brain neurons.
Evidence indicates that two forms of albumin, differing in their affinities for diand trivalent cations, are present in both serum and cerebrospinal fluid (CSF) of healthy persons as well as AD patients (Giick, 1990; Giick & Shamoo, 1990). One form of albumin (designated as altered albumin) apparently has an increased affinity for A1, a decreased affinity for Mg, and an increased ability to cross the blood-brain barrier (BBB), in comparison to the other form of albumin (designated as normal albumin). The ratio of altered to normal albumin was found to be higher for AD patients than for control patients in both serum and CSF. Altered albumin presumably contributes to the progression of AD by competing favorably with normal albumin in binding to brain neurons. Increased binding of altered albumin to brain neurons would both facilitate A1 uptake and impede Mg uptake, thereby contributing to the progression of Alzheimer's disease.
Indirect evidence suggests that the amino acid sequence of altered albumin is unchanged from that of normal albumin, yet its tertiary structure is somehow modified (Giick, 1990). Such a paradox could be explained by the presence of another molecule, which binds to albumin, thereby altering its tertiary structure. In fact, albumin binds a number of different molecules, including fatty acids, amino acids, and proteins (Carter et al., 1989), and changes shape in response to ligand binding (Gersten & Hearing, 1989).
Albumin exists as a single polypeptide, 585 amino acids (aa) long, divided into three structurally homologous domains: I, II, and III. These domains are further divided into the following subdomains and connecting regions: IA (aa 1-100), alpha helix (aa 101-124), IB (aa 125-176), non-helical segment (aa 177-200), IIA (aa 201-288), alpha helix (aa 289-316), IIB (aa 317-368), non-helical segment (aa 369-392), IliA (aa 393-486), alpha helix (aa 487-514), and IIIB (aa 515-585) (Dugaiczyk et al., 1982;Carter et al., 1989). Carter & He (1990) have reported extensive folding within each of the subdomains of albumin, as well as the close association of IIA with both IA and IB, and have noted that the majority of the binding in albumin for a variety of substances occurs within subdomains IlA and IIIA.