The brains of people with Alzheimer’s are riddled with Amyloid precursor protein (short APP) that form Amyloid plaque.
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.
“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.”
But amyloid in and of itself doesn’t really explain what goes wrong in the Alzheimer’s brain. “There has been a lot of attention on amyloid, but it seems it is not a simple matter of amyloid as the sole culprit,” Bush said. For one thing, trials of drugs designed to target and clear amyloid plaques haven’t worked as intended.
In fact, the disease is also complicated by high concentrations of metals, including iron that builds up inside neurons and zinc that accumulates within the amyloid plaques outside of those brain cells. And studies have also linked the loss of other iron oxidases to pathological iron accumulation and neurodegenerative diseases characterized by dementia. “If iron is left unbridled in its soluble form, it can cause nerve death and damage,” Rogers said.
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 amyloid 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.”
Read more at Physorg.com