Iron Overload Inside Brain Cells Linked To Alzheimer's Disease
September 13, 2010
Adapted from Cell Press
In people with Alzheimer's, the brain becomes riddled with clumps of protein, forming what are known as amyloid plaques. Now, a report appearing in the September 17th, 2010 print issue of Cell appears to have found a function for the amyloid precursor protein (APP for short) that yields the prime ingredient in those plaques.
It turns out that APP is an iron oxidase whose job it is to convert iron from an unsafe form to a safe one for transport or storage. When APP fails to function properly, as it does in Alzheimer's disease, iron levels inside neurons mount to toxic levels.
"This opens a big window on Alzheimer's disease and iron metabolism," said Ashley Bush of The Mental Health Research Institute, University of Melbourne.
"Although people have attributed several important physiological roles to APP," added Jack Rogers of Harvard Medical School, "this now gives us an idea of what this critical protein does to underpin its role in iron metabolism."
"If iron is left unbridled in its soluble form, it can cause nerve death and damage," Rogers said.
After 10 years of work, it appears Bush's and Roger's teams have connected the dots from the abnormal exchange of zinc to amyloid pathology and iron accumulation in Alzheimer's disease. "It's a sequence of dominoes falling onto each other," Bush said.
Mice lacking APP become vulnerable to dietary iron, which causes the unsafe, oxidative form of iron to build in the animals' neurons, they show. Finally, they have shown that zinc in amyloid blocks APP's normal iron-balancing activities in the Alzheimer's brain.
Based on the new evidence, the researchers propose that elevated iron in the Alzheimer's brain summons further APP production. But that APP—generated for the purpose of exporting iron—gets disabled by high levels of zinc that dissociate from the amlyoid plaques.
The findings suggest that zinc may be an ideal target in the fight against Alzheimer's disease, the researchers say. In fact, studies in animals and early, short-term clinical trials of zinc-ionophore drugs including clioquinol and PBT2 in people with Alzheimer's disease have so far produced promising results. PBT2 is slated for further testing.
"Our findings authenticate zinc as a target," Bush said. "It really makes it look like an attractive place to hit." Although Rogers said that he doesn't want to raise hopes for an Alzheimer's cure too high, "this is definitely an important step in getting to a therapy to retard the Alzheimer's disease process."
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