The DR is out

Abstract

Five years after a Genentech Inc. team proposed that the receptor DR6 might be involved in Alzheimer's disease, the company and The Rockefeller University have concluded that the proapoptotic pathway is unlikely to affect the most overt feature of the disease-amyloid plaque formation.The Roche unit said that the new findings 1,2 mark the stopping point for its discovery efforts to target DR6 (tumor necrosis factor receptor superfamily member 21; TNFRSF21) in AD. Although the company is backing off DR6, the academics involved in the work think further studies with better disease models are warranted.DR6 is a member of a family of cell surface receptors that activates caspases-intracellular proapoptotic proteases-when neurons are deprived of trophic factors such as nerve growth factor (NGF) or brainderived neurotrophic factor (BDNF).In 2009, Genentech discovered an interaction between DR6 and amyloid precursor protein (APP), 3 a neuronal surface protein that undergoes a series of proteolytic cleavages to yield the b-amyloid (Ab) fragment. Ab aggregates form the amyloid plaques that are the hallmarks of AD and are thought to be a main upstream trigger for neurodegeneration. The group, led by then-CSO Marc Tessier-Lavigne, found that DR6 was activated by a fragment of APP left behind after the proteolytic processing formed Ab. 4 Tessier-Lavigne is now a professor and president at The Rockefeller University.Because activation of DR6 by the stray APP fragment led to neuronal apoptosis, the next question was whether DR6 activation played a role in Ab toxicity."We set out to test a specific hypothesis about the potential role of DR6 in an APP-driven model of AD, " said team leader and Genentech senior scientist Robby Weimer. "The conclusion from our results is that we didn't find a role for DR6 in amyloid formation, synapse loss or behavior consequence. Our take home is that DR6 doesn't represent a good target for APP-driven AD pathology. " Death receptor deadThe hope was that DR6 inhibition might enhance neuronal branching and thus counteract the neurotoxic effects of Ab. However, the new findings suggest that will not be the case.In two mouse models of AD in which overproduction of Ab leads to disease, DR6 deletion increased branching of mature neurons in some brain regions compared with no alteration. However, DR6 deletion did not reduce plaque formation or the behavioral and cognitive consequences of Ab toxicity. Results were reported in The Journal of Neuroscience.Weimer and Tessier-Lavigne said that the findings indicate that one of APP's normal functions outside of AD may be to interact with DR6 to control neuronal branching in the adult nervous system. However, this process likely occurs independently of the abnormal proteolytic processing of APP that leads to AD."It seems that APP has multiple functions, " said Weimer. "Its normal physiological function could be through DR6. We did find evidence for DR6 and APP acting together in the mature nervous system to regulate synapse sensitivity. "Tessier-Lavigne said t...