Scientists from UT Southwestern Medical Center have identified a step that encourages buildup of the key protein called beta-amyloid that encourages the spread of the disease .
In Alzheimer's disease, an enzyme that has many other essential roles produces too much beta-amyloid. As a result, simply blocking the whole enzyme knocks out many of its other functions - which is fatal to the organism.
Using cultured human and mouse cells, as well as test-tube assays, UT Southwestern researchers singled out how just one portion of the enzyme, a protein called nicastrin, is involved in the pathway that produces beta-amyloid, thereby leading to Alzheimer's disease. They hope next to work on ways to specifically block nicastrin. The study appears in the August 12 issue of the journal Cell.
Nicastrin is a large protein that is a component of an enzyme called gamma-secretase, which is lodged in the cell's membrane. When it is at the cell surface, nicastrin sticks out into the area outside the cell. It has been thought to play a key role in the creation of a protein called amyloid-beta - the prime suspect for the damage Alzheimer's does to the brain - but the exact mechanism was unknown.
Researchers had found that nicastrin binds to several proteins lodged in the cell's membrane, including one called amyloid precursor protein, or APP. Nicastrin then guides membrane-bound proteins to the active area of gamma-secretase, which then splits the proteins. APP, for example, is chopped into two parts: amyloid-beta, which is then shipped to the outside of the cell, and another part that remains inside. Amyloid-beta forms the plaques seen in brains afflicted with Alzheimer's.
Now that nicastrin's function has been ascertained, it opens a way to block just the splitting of APP, leaving all the enzyme's other functions intact. For instance, it may be possible to generate chemical compounds that specifically prevent nicastrin from latching on to APP. If APP doesn't attach to nicastrin, APP remains intact and harmless. Meanwhile, nicastrin would be free to bind all the other essential proteins that it works on.