Iron, brain ageing and neurodegenerative disorders

Iron is an essential cofactor for many proteins that are involved in normal neuronal tissue function, but there is increasing evidence that iron accumulation in the brain can cause a vast array of CNS disorders.Global iron homeostasis is regulated at the level of iron absorption from the gastrointestinal tract. This involves a series of molecular interactions between proteins that include the haemochromatosis gene product HFE, transferrin, the transferrin receptor and iron regulatory proteins in the crypts of Lieberkühn.The brain has several characteristics that make it unique with regard to iron metabolism. It resides behind a vascular barrier — the blood–brain barrier — which limits its access to plasma iron. Also, the concentration of iron varies considerably between different brain regions: regions that are associated with motor functions tend to have more iron than non-motor-related regions.Iron seems to accumulate in the brain as a function of age. This process is quite specific, and it involves the accumulation of iron-containing molecules in certain cell types, particularly in brain regions that are preferentially targeted in neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD).PD is associated with increased iron accumulation in the substantia nigra. Proposed mechanisms for iron-induced cell damage in PD include enhanced generation of reactive oxygen species and an increase in oxidative stress and protein aggregation. This includes the aggregation of α-synuclein, which is one of the main components of Lewy bodies — one of the pathological hallmarks of PD.In AD, iron accumulation in the brain occurs without the normal age-related increase in ferritin, and this increases the risk of oxidative stress. Iron might also have a direct impact on plaque formation through its effects on amyloid precursor protein processing.Iron accumulation has also been implicated in several other neurological diseases, including congenital aceruloplasminaemia, Friedreich's ataxia, neuroferritinopathy, neurodegeneration with brain iron accumulation and restless legs syndrome.Metal chelators are being developed as a new therapeutic strategy for the treatment of PD, AD and other neurodegenerative disorders that involve iron misregulation.If we can understand the timing of iron mismanagement in relation to the progression of neuronal loss in neurodegenerative diseases and during ageing, this might raise the possibility of monitoring iron changes as a marker of disease progression, and perhaps even pre-clinical diagnosis in conditions where iron mismanagement is an early event.