The APP-death-receptor Mechanism Genentech scientists have discovered a novel mechanism that nerve cells use to self destruct when deprived of survival factors ("trophic factors"). Nerve cells carry two proteins, APP (Amyloid Precursor Protein) and DR6 (Death Receptor 6). When they are deprived of trophic factors, they activate the APP protein by cleaving it (illustrated with the scissors) to release the N-APP fragment. N-APP then binds and activates DR6, which triggers degeneration of the nerve cell and nerve fiber. This self-destruction mechanism is used to remove excess nerve cells and nerve fibers during embryonic and fetal development.

This mechanism may contribute to the initiation or progression of Alzheimer's disease. It has been known for 20 years that the APP protein is involved in Alzheimer's, but how it is involved remains uncertain. The discovery that APP is part of a normal physiological self-destruction mechanism has led Genentech scientists to propose that this mechanism is hijacked by Alzheimer's disease and contributes to the degeneration of nerve cells and nerve fibers that occurs in the disease.

Nerve Fiber Micrographs These micrographs illustrate how the N-APP protein fragment triggers degeneration of nerve fibers. The left panel shows healthy nerve fibers grown in petri dishes, labeled with a green dye. The right panel shows nerve fibers that have degenerated after being exposed to N-APP. Such degeneration may contribute to the pathophysiology of Alzheimer's disease.