Figure 1

Distributional route of ascorbic acid (AA) from blood into central nervous system to serve as a co-factor for TET enzymes in neuronal nuclei: Plasma-borne AA does not permeate the BBB, but is reflected off the inside surface of the capillary endothelium due to the restriction to diffusion offered by the tight junctions and luminal membrane (upper left). Rather, AA reaches brain by a circuitous route involving (sequentially) the CP, CSF and ependyma. Thus, AA is transferred (unfilled arrow) from leaky blood vessels in CP through epithelial cells into ventricular CSF by the sodium-dependent vitamin C transporter 2 (SVCT-2) in the basolateral membrane. From CSF, AA diffuses freely through permeable gap junctions in the ependyma into brain extracellular fluid. There, AA reaches neurons and is greatly concentrated by the actively-transporting SVCT-2 in neuronal membranes. Upon accessing the neuronal cytoplasm, AA diffuses to and penetrates the nuclear membrane. Within the nucleoplasm, AA acts as an essential co-factor for TET (with Fe⁺⁺ and α-KG) to oxidize certain methyldeoxycytidine (mdC) molecules in the same-strand DNA to hydroxymethyldeoxycytidine (hmdC). hmdC can be further oxidized and removed from DNA by thymine DNA glycosylase with subsequent DNA repair as explained in the text. The SVCT-2 transport systems for AA in CP and neurons act not only as concentrative systems for AA in CSF and neurons but also homeostatic systems that keep the millimolar concentration of AA in neurons relatively constant.