While iron (Fe) is essential for normal brain function its accumulation in the aging brain is associated with neurodegeneration. The mechanism of accumulation is still unclear. Our recent studies indicated that entry of transferrin (Tf)-bound and free iron into the CNS is determined by (i) initial rapid sequestration by brain capillaries (BBB) and choroid plexus (CP), and (ii) subsequent controlled and slow release from vascular structures into brain interstitial fluid (ISF) and cerebrospinal fluid (CSF). In addition, our pilot data suggest that iron is rapidly cleared from brain into blood across the blood-brain barrier mainly by a Tf-medicated mechanism. Based on these preliminary data, we hypothesize that influx of iron across the blood-brain barrier and CP is a two-step process that requires both Tf receptor (TfR) and DMT1 (divalent metal transporter 1) with DMT1 being a rate limiting step, while efflux of Fe from the CNS is a one-step process that depends on Tf route and requires TfR at the blood-brain barrier. We further hypothesize that imbalance between iron CNS influx and efflux transport mechanisms, due mainly to reduced clearance at the vascular CNS barriers leads to its accumulation in the aging brain. There are two Aims. 1. To determine the role of Tf-mediated and non-Tf route for Fe efflux from CNS and the retention mechanism for Fe in CNS in bold type and DMT1 mutant Belgrade rats at selective ages. 2. To determine the kinetics of Tf and non-Tf mediated Fe influx across blood-brain barrier and CP in wild type and Belgrade rats at selective ages.
These Aims will be achieved by using the brain perfusion and clearance techniques and the Belgrade rat (b/b) since it is a physiological knock out for DNT1. The kinetic parameters of Tf and non Tf bound Fe will be determined in b/b/ and control rats to establish the role of DMT1 in the influx and efflux of Fe at the blood-brain barrier and CP. Similar studies in control rats at selected ages will determine age related changes. Relative levels of TfR and DMT1 at blood-brain barrier and CP will be determined by standard molecular techniques to complement the transport studies. This study will help us understand the roles of DMT1 and TfR at the BBB and CP with respect to iron accumulation in the brain, associated neurodegenerative effects, and identify potential targets for future development of brain iron lowering strategies.
| Deane, R; Sagare, A; Zlokovic, B V (2008) The role of the cell surface LRP and soluble LRP in blood-brain barrier Abeta clearance in Alzheimer's disease. Curr Pharm Des 14:1601-5 |
| Deane, Rashid; Zlokovic, Berislav V (2007) Role of the blood-brain barrier in the pathogenesis of Alzheimer's disease. Curr Alzheimer Res 4:191-7 |
