title: 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.
abstract: 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.
authors.affiliation: Departments of Biomedical Imaging, Neuroscience, and Pathology, Genentech Inc., South San Francisco, California 94080, Stanford Behavioral and Functional Neuroscience Laboratory, Stanford University, Stanford, California 94305, and Laboratory of Brain Development and Repair, The Rockefeller University, New York, New York 10065.
authors.forename: Dara Y
authors.initials: DY
authors.lastname: Kallop
authors.forename: William J
authors.initials: WJ
authors.lastname: Meilandt
authors.forename: Alvin
authors.initials: A
authors.lastname: Gogineni
authors.forename: Courtney
authors.initials: C
authors.lastname: Easley-Neal
authors.forename: Tiffany
authors.initials: T
authors.lastname: Wu
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Jubb
authors.forename: Murat
authors.initials: M
authors.lastname: Yaylaoglu
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Shamloo
authors.forename: Marc
authors.initials: M
authors.lastname: Tessier-Lavigne
authors.forename: Kimberly
authors.initials: K
authors.lastname: Scearce-Levie
authors.forename: Robby M
authors.initials: RM
authors.lastname: Weimer
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000502:physiology*; D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D002490:Central Nervous System / Q000166:cytology* / Q000254:growth & development; D003216:Conditioning, Operant / Q000502:physiology; D049229:Dendritic Spines / Q000502:physiology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005239:Fear / Q000523:psychology; D005911:Gliosis / Q000473:pathology; D006801:Humans; D017403:In Situ Hybridization; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000502:physiology; D009434:Neural Pathways / Q000502:physiology; D058225:Plaque, Amyloid / Q000473:pathology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000502:physiology*
chemical_list: D016564:Amyloid beta-Protein Precursor; D018124:Receptors, Tumor Necrosis Factor; C114109:TNFRSF21 protein, human
keywords: APP; Alzheimer's; DR6