Marked for Death?
Authors: Davenport R. John 
Published: August 2003

SINGAPORE
--Everyone knows that Alzheimer's disease scars patients and families, but now scientists at the Asia Pacific Conference and Exhibition on Anti-Ageing Medicine 2002, held here from 23 to 26 June, say that the affliction wounds particular proteins as well. If such nicks debilitate the molecules, they could explain how a key protein implicated in Alzheimer's disease triggers nerve cell death.

Alzheimer's brains are riddled with clumps of a protein called β amyloid. Many researchers believe that the protein underlies the disease, but its role is unclear (see
"Detangling Alzheimer's Disease"
). Allan Butterfield, a chemist at the University of Kentucky in Lexington, and colleagues have suggested that β amyloid generates free radicals that cause the oxidative damage observed in proteins, DNA, and membranes of Alzheimer's brains. In the new work, the team sought to identify proteins that succumb to such blows in Alzheimer's disease.

To find the most heavily marred proteins, the researchers extracted brain proteins from people with and without the disease. Next they separated the proteins according to size and electric charge and fixed the array of proteins to a solid support. After dousing the material with an antibody that binds to carbonyl groups, common products of oxidative damage, the scientists looked for spots with more antibodies in the samples from Alzheimer's patients than in control samples. They found six such proteins, and they subsequently recovered and identified them.

If carbonyl groups debilitate these proteins, the researchers reasoned, such damage might explain why nerve cells go haywire in Alzheimer's disease. Two of the proteins--creatine kinase and α enolase--help generate high-energy molecules that nerve cells require to function normally and to fight off damage. A third protein, called collapsin, directs growth of nerves so that they connect properly. Two other proteins--glutamine synthetase and glutamate transporter protein--prevent overload of a chemical called glutamate. This neurotransmitter normally enables nerves to send signals to one another, but if it overaccumulates, it can trigger too much firing, which causes ions to build up to deadly concentrations inside neurons. The sixth protein snips a tag called ubiquitin off of other proteins. Ubiquitin attaches to damaged proteins and marks them for the cellular trash heap. If ubiquitin isn't recycled, it can't send other garbage proteins to the dump, resulting in an accumulation of cellular junk.

The team doesn't yet know if the modified proteins from Alzheimer's brains can't function, but previous studies by the group suggest that neurons in Alzheimer's disease carry crippled creatine kinase and glutamate transporter. Further studies are needed to show that free radicals generated by β amyloid cause the damage, but Alzheimer's researcher Akhlaq Farooqui of Ohio State University, Columbus, calls this "an important finding." He says that the small number of modified proteins in this genomewide survey suggests that β amyloid concentrates damage on just a few molecules. Perhaps, suggests Butterfield, antioxidant treatments could prevent this damage, leaving nerve cells--and elderly patients--with a clean bill of health.

--R. John Davenport

Further Reading

Asia Pacific Conference and Exhibition on Anti-Ageing Medicine 2002
http://www.antiaging2002.org/index.shtml