SOUTH SAN FRANCISCO, Calif.—The mechanism of action of a heretofore puzzling protein thought to play a key role in Alzheimer's disease has been unraveled by scientists at Genentech and the Salk Institute.
In an article that appeared in February in Nature, the team, led by Genentech's Dr. Marc Tessier-Lavigne, reported that _-amyloid precursor protein (APP) and death receptor 6 (DR6) activate a widespread caspase-dependent self-destruction program in the brain.
Tessier-Lavigne, executive vice president of research drug discovery at Genentech, notes that in the field of Alzheimer's disease, "it is well known that a bad actor in the brain is a protein called APP, and what we found is a new twist on our understanding of what APP does."
APP is a large protein that sits in the cell membrane, and for many years, the field has focused on a piece of the protein near the cell membrane called Abeta.
"It's been argued that Abeta is toxic and contributes to the degeneration that occurs in the disease. What we found is that a different portion of the APP molecule, which we call N-APP, actually can trigger the death and degeneration of neurons, and we've figured out the mechanism through which it triggers that degeneration. So we believe that this could be involved in either the initiating or helping the progression of Alzheimer's disease," Tessier-Lavigne states.
The new understanding about APP came about as an accident, he says, during the course of research into the normal process of nerve cell degeneration that occurs as embryos develop in the womb. When the brain and spinal cord are first being formed, excess numbers of nerve cells are generated which are later killed off in the natural process of forming the nervous system. Genentech researchers discovered that DR6 is responsible for this normal embryonic self-destruction mechanism. But when Tessier-Lavigne and his team went looking for the substance that activated DR6 to prune back embryonic nerve cells, they were surprised to learn that it was APP.
Genentech recently decided to place new emphasis on neuroscience because, in Tessier-Lavigne's words, "We think the time is right now because the unmet need is enormous in both neurological and psychiatric disease, and the science has been breaking open and accelerating over the past several years." Tessier-Lavigne was recruited to join the company and help lead this new research effort.
"We're tackling a number of other neurological diseases apart from Alzheimer's," he notes, ticking off Parkinson's disease, ALS and glaucoma. "And recently," he adds, "we've started to expand beyond neurodegenerative diseases into other areas, including spinal cord injury, pain and other psychiatric and affective disorders. So, while Alzheimer's is an important focus for us, it's really just the beginning of a larger effort we're mounting.
"We place a really big effort on understanding the basic biology of the mechanisms and diseases that we're studying, trying to add fresh insights and understand them in-depth, not just try to make drugs against specific targets," Tessier-Lavigne adds. "This is the approach that we take in all of our therapeutic areas, of course, and neuroscience is no exception, but I think that makes us stand out from many other companies.
"This new understanding provides us with a number of new therapeutic targets," he adds. "We can try to prevent the initiation or progression of the disease by blocking the portion of the APP molecule that we've identified, or some of the other downstream signaling mechanisms that we've pinpointed, as well. It provides us with a whole host of new entry points to try to block or mitigate the effects of the disease."
