The Transcobalamin (TC) Codon 259 Genetic Polymorphism Influences Holo-TC Concentration in Cerebrospinal Fluid from Patients with Alzheimer Disease

Two proteins bind vitamin B12 in plasma: haptocorrin (transcobalamin I) and transcobalamin (transcobalamin II; TC). The latter is the critical transporter that delivers vitamin B12 to peripheral tissues. TC carries one-third of the circulating B12 (holo-TC), but most TC is unsaturated (apo-TC) (1)(2). Polyacrylamide gel electrophoresis has revealed two common TC isotypes, M and X, and two rare variants, S and F (3)(4), that may influence the cellular availability of vitamin B12 (5)(6). The phenotypic variability is a multifactorial phenomenon that probably includes cell-type-specific processing of translated TC (5), but the substitution of proline (P) for arginine (R) at codon 259 of the TC gene is the major determinant of the TC variability, at least in Caucasians (5)(7), and affects TC concentrations in plasma (5)(8). Most 259PP individuals have the TC M phenotype, whereas most 259RR individuals have the X phenotype.Vitamin B12 is essential for the function of the central nervous system (CNS) (9). Little is known about vitamin B12 transport in the human brain, but early in vitro data indicate that TC plays a central role (10). Cerebrospinal fluid (CSF) contains both haptocorrin and TC, with the latter predominating (11). The CSF:plasma ratio of TC is high compared with other plasma proteins (12), which suggests an active transport mechanism or synthesis by cells in the CNS. Cultured astrocytes have been shown to produce and secrete TC in vitro (13), indicating that at least some of the TC in CSF originates from within the CNS. However, because vitamin B12 is not synthesized in human cells, it must enter the brain and CSF from the blood across the blood–brain barrier, conceivably via interaction between holo-TC and the TC receptor. In the present investigation, …