Genentech Finds Alzheimers “death Receptor” Target For Drugs
The particle, dubbed “death receptor 6,” plays a previously unknown role in sparking mass cell death in Alzheimers disease, said Marc Tessier-Lavigne, executive vice president of research drug discovery at the South San Francisco, California-based biotechnology company. DR6 does this by binding to a fragment, called N-APP, of amyloid precursor protein, a known bad actor in the brain degeneration of Alzheimers.
The interaction of the death receptor with N-APP may play an innocent role in a developing brain by pruning neurons until there is just enough for normal brain function, said Tessier- Lavigne. In Alzheimers disease, this process gets hijacked and triggers runaway cell suicide that destroys memory and cognition. The discovery may offer new targets for drug development to slow degenerative brain diseases, he said.
“The real interest arose when we said, Here is a receptor – - what activates it?” Tessier-Lavigne said in a telephone interview. “We fell off our chairs when we found that what activates it is none other than this N-APP protein, a key component of the self destruction pathway” in Alzheimers disease.
The findings were reported by Tessier-Lavigne and colleagues at Genentech and the Salk Institute in La Jolla, California in the journal Nature, posted online today.
Bad Actor
DR6 was once thought to play a role in the immune system and hadnt previously been implicated as a “bad actor” in Alzheimers disease or other degenerative brain disorders, Tessier-Lavigne said. When scientists blocked the interaction of DR6 and the N fragment of APP, they delayed suicide of the brains neurons for several days, he said, sparking hope for future therapeutic potential.
Genentech is working on at least three early prototypes including laboratory designed antibodies and chemically synthesized compounds that would block DR6, N-APP or another protein involved in cell suicide known as caspase 6. Blocking any one of these three avenues might delay cell death in Alzheimers disease, Tessier-Lavigne said.
The hijacking of normal cell pruning also may occur in Huntingtons disease, a neurological disorder that causes dementia, and traumatic brain injury, giving the findings potentially broader application, he said.
Genentechs findings, stemming from mouse and test tube experiments, are years away from producing a drug for testing in humans, Tessier-Lavigne said. The discovery is the first major neuroscience finding since Genentech three years ago announced a renewed thrust into brain research as a complement its core cancer business.