Hospital Dr Issue 9 - Irish Medical Information

Researchers in Melbourne believe they have finally figured out the function for the protein that builds up in the brains of people with Alzheimer’s disease.

It has long been known that amyloid precursor protein (APP) forms plaques in Alzheimer’s patients leading to brain cell death and, ultimately, dementia. However, scientists have struggled to understand whether APP has any positive role to play in cell biology.

A team at the University of Melbourne believes APP is an iron oxidase - a protein 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.”

Previous studies had hinted at this discovery. It was previously reported that the RNA template for the APP protein includes an iron-responsive element. When iron levels rise, cells ramp up their APP production.

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 characterised by dementia. “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.

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."

Reference:

Cell, September 2010. Epub ahead of print