RT Journal Article
SR Electronic
T1 A Death Receptor 6-Amyloid Precursor Protein Pathway Regulates Synapse Density in the Mature CNS But Does Not Contribute to Alzheimer's Disease-Related Pathophysiology in Murine Models
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 6425
OP 6437
DO 10.1523/JNEUROSCI.4963-13.2014
VO 34
IS 19
A1 Dara Y. Kallop
A1 William J. Meilandt
A1 Alvin Gogineni
A1 Courtney Easley-Neal
A1 Tiffany Wu
A1 Adrian M. Jubb
A1 Murat Yaylaoglu
A1 Mehrdad Shamloo
A1 Marc Tessier-Lavigne
A1 Kimberly Scearce-Levie
A1 Robby M Weimer
YR 2014
UL http://www.jneurosci.org/content/34/19/6425.abstract
AB Recent studies implicate death receptor 6 (DR6) in an amyloid precursor protein (APP)-dependent pathway regulating developmental axon pruning, and in a pruning pathway operating during plastic rearrangements in adult brain. DR6 has also been suggested to mediate toxicity in vitro of Aβ peptides derived from APP. Given the link between APP, Aβ, and Alzheimer's disease (AD), these findings have raised the possibility that DR6 contributes to aspects of neurodegeneration in AD. To test this possibility, we have used mouse models to characterize potential function(s) of DR6 in the adult CNS and in AD-related pathophysiology. We show that DR6 is broadly expressed within the adult CNS and regulates the density of excitatory synaptic connections onto pyramidal neurons in a genetic pathway with APP. DR6 knock-out also gives rise to behavioral abnormalities, some of which are similar to those previously documented in APP knock-out animals. However, in two distinct APP transgenic models of AD, we did not observe any alteration in the formation of amyloid plaques, gliosis, synaptic loss, or cognitive behavioral deficits with genetic deletion of DR6, though we did observe a transient reduction in the degree of microglial activation in one model. Our results support the view that DR6 functions with APP to modulate synaptic density in the adult CNS, but do not provide evidence for a role of DR6 in the pathophysiology of AD.