Amyloid precursor protein (APP) mRNA has an iron response element (IRE) in the 5′ untranslated region. Iron regulatory 1 (IRP1) and and iron regulatory protein 2 (IRP2) when bound to the IRE in the 5′ untranslated regiondestablize transcripts of iron regulated proteins. IRP1 and IPR2 when bound to the IRE in amyloid precursor protein mRNA decrease translation of APP. Iron decreases levels of IRP1 and IRP2. A point of iron chelators in Alzhemeir’s disease is by decreasing iron levels to increase levels of IRP1 and IRP2 thereby decreasing transcripition of APP.
APP is the precusor of amybloid beta protein. Amyloid betacan form plaques which are associated with Alzheimer’s disease. Iron chelators by decreasing APP levels would decrease levels of amyloid beta protein which was thought for decades to be a very good thing. Very effective treatments for Alzheimer’s appeared imminent.
A very serious difficulty arose. Drugs that reduce levels of amyloid beta do not treat or slow the progression of Alzheimer’s disease.
APP can looked at from a different angle. Amyloid precursor protein when ablatedincreases iron retention in cells by decreasing iron export. Loss of tight control of APP translation not high levels of APP could be what is causing iron retention in neurons.
What I have been arguing is that IRP1 is dysregulated in a range of neurological illnesses, such as Alzheimer’s and that this can lead to iron accumulation in neurons and cell death. Tight control of iron levels, not reducing iron levels via iron chelation, could be part of a treatment for various neurological illnessse such as Alzheimer’s disease.
A meta-analysis indicate that serum iron is significantly lower in Alzheimer’s patients than in controls. Supplmental iron carbonyl given three time a day could be part of a treatment for Alzheimer’s disease. The goal, of course, would not be high iron levels but rather tightly regulated levels of IRP1 and IRP2. Iron homeostasis could be upset in Alzheimer’s disease which is a much different way of loooking at iron than ‘iron is toxic’ in Alzheimer’s disease.
In Friedreich ataxiairon-sulfur clusters are not formed, due to deficiencies in frataxin which results in iron accumulation in mitochondria. The relevant point is that problems in iron-sulfur cluster formation can be associated with iron accumulation in mitochondria and iron toxicity. The point I have been making is that there are difficulties in synthesizing iron-sulfur clusters in many neurological illnesses due to dysregulation of the transsulfuration pathway which synthesizes L-cysteine. L-cysteine supplies sulfur for iron-sulfur cluster formation.
Iron chelatorsare now being investigated as treatments for Alzheimer’s disease and Parkinson’s disease. If iron is being accumulated in cells in Alzheimer’s disease and Parkinson’s disease due to difficulties in iron-sulfur cluster formation then iron chelators would not be appropriate treatments. Iron-sulfur cluster formation is increased by supplemental iron. Iron chelators by decreasing iron would decrease iron–sulfur cluster formation leading to iron accumulation in mitochondria and iron toxicity.
Iron overload in various regions of the brain has been postulated to be involved in the pathological mechanism of Alzheimer’s disease. Iron overload in the brain may very well be involved in the etiology of Alzheimer’s disease but iron overload in the brain in Alzheimer’s disease would not be due to too much iron in the diet.
A meta-analysis indicates that serum iron levels are significantly lower in Alzheimer’s disease patients than in healthy controls. Another meta-analysis also indicates that serum iron is significantly lower in patients with Alzheimer’s disease than in healthy controls.
Loss of control over iron metabolism rather that just ‘too much iron’ could be why iron can have negative effects in Alzheimer’s disease. Treatment in AD would demand that control be regained over iron metabolism. Iron chelators have been proposed as a treatment for Alzheimer’s disease. Iron chelators, however, would not be useful in terms of regaining control over iron metabolism. Iron chelators could have negative effects in AD.
Iron chelators are being clinically tested in a number of neurodegenerative illnesses such as Alzheimer’s and Parkinson’s disease . I do not think iron chelation is going to work. In fact I think iron chelators will make Alzheimer’s and Parkinson’s worse. I very much hope I am mistaken. The difficulty isn’t iron per se but rather dysregulation of iron regulated biological processes. Sensible ideas are wrong all the time. Iron chelation is a very sensible approach to treatment of Alzheimer’s and Parkinson’s which I think is going to be disastrous.