title: The systemic iron-regulatory proteins hepcidin and ferroportin are reduced in the brain in Alzheimer's disease.
abstract: BACKGROUND
  The pathological features of the common neurodegenerative conditions, Alzheimer's disease (AD), Parkinson's disease and multiple sclerosis are all known to be associated with iron dysregulation in regions of the brain where the specific pathology is most highly expressed. Iron accumulates in cortical plaques and neurofibrillary tangles in AD where it participates in redox cycling and causes oxidative damage to neurons. To understand these abnormalities in the distribution of iron the expression of proteins that maintain systemic iron balance was investigated in human AD brains and in the APP-transgenic (APP-tg) mouse.
  
  
  RESULTS
  Protein levels of hepcidin, the iron-homeostatic peptide, and ferroportin, the iron exporter, were significantly reduced in hippocampal lysates from AD brains. By histochemistry, hepcidin and ferroportin were widely distributed in the normal human brain and co-localised in neurons and astrocytes suggesting a role in regulating iron release. In AD brains, hepcidin expression was reduced and restricted to the neuropil, blood vessels and damaged neurons. In the APP-tg mouse immunoreactivity for ferritin light-chain, the iron storage isoform, was initially distributed throughout the brain and as the disease progressed accumulated in the core of amyloid plaques. In human and mouse tissues, extensive AD pathology with amyloid plaques and severe vascular damage with loss of pericytes and endothelial disruption was seen. In AD brains, hepcidin and ferroportin were associated with haem-positive granular deposits in the region of damaged blood vessels.
  
  
  CONCLUSIONS
  Our results suggest that the reduction in ferroportin levels are likely associated with cerebral ischaemia, inflammation, the loss of neurons due to the well-characterised protein misfolding, senile plaque formation and possibly the ageing process itself. The reasons for the reduction in hepcidin levels are less clear but future investigation could examine circulating levels of the peptide in AD and a possible reduction in the passage of hepcidin across damaged vascular endothelium. Imbalance in the levels and distribution of ferritin light-chain further indicate a failure to utilize and release iron by damaged and degenerating neurons.
authors.affiliation: John Van Geest Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge CB2 0PY, UK. rr224@cam.ac.uk.
authors.forename: Animesh Alexander
authors.initials: AA
authors.lastname: Raha
authors.forename: Radhika Anand
authors.initials: RA
authors.lastname: Vaishnav
authors.forename: Robert Paul
authors.initials: RP
authors.lastname: Friedland
authors.forename: Adrian
authors.initials: A
authors.lastname: Bomford
authors.forename: Ruma
authors.initials: R
authors.lastname: Raha-Chowdhury
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D064451:Hepcidins / Q000378:metabolism*; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism; D019581:Neuropil / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; C578702:HAMP protein, human; C579599:Hamp protein, mouse; D064451:Hepcidins; D020033:Protein Isoforms; D000098742:Ferroportin