The function for the amyloid precursor protein that yields the prime ingredient in amyloid plaques, which leads to Alzheimer's disease has been found by scientists.
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.
AdvertisementWhen 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. This now gives us an idea of what this critical protein does to underpin its role in iron metabolism," added Jack Rogers of Harvard Medical School.
"There has been a lot of attention on amyloid, but it seems it is not a simple matter of amyloid as the sole culprit," said Bush.
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," said Rogers.
After 10 years of work, the researchers have apparently 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," said Bush.
They show that APP is a bona fide iron oxidase, with properties much like the best-known iron oxidase (called ceruloplasmin), which is not expressed in neurons.
Loss of APP in cells and primary neurons causes iron levels to build, while increasing APP promotes the export of iron out of cells.
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, said the researchers.
The study appears in the upcoming print issue of Cell.
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