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 A␤ peptides derived from APP. Given the link between APP, A␤, 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.

Loss of dual leucine zipper kinase signaling is protective in animal models of neurodegenerative disease

“…JNK pathway activity was also elevated in two transgenic mouse strains that model specific aspects of AD, PS2APP and Tau P301L (24)(25)(26), at ages greater than 6 months ( , E and F), indicating that the aberrant JNK pathway activity was similarly limited to neurons in these models. In postmortem central nervous system (CNS) tissues from patients with either early-stage AD or confirmed AD, p-c-Jun immunostaining was significantly elevated in hippocampal neurons (Fig.…”

“…Dlk deletion is beneficial in two mouse models of AD In AD, reductions in dendritic spine densities are greatest within close proximity to amyloid plaques (35), which can be recapitulated in mouse models (24,(36)(37)(38)(39). On the basis of previous work, this end point can serve as an indicator of synaptic loss and provides a valuable measure of degenerative processes because neuronal loss is not a common feature of amyloid precursor protein (APP) transgenic mouse models of AD (40,41).…”

TREM2, Microglia, and Neurodegenerative Diseases

“…Not only are microglia more abundant at 2 years of age, but they acquire a gene expression profile akin to that observed in microglia from brains with Ab plaque pathology or from spinal cords of ALS mouse models [135]. Aged microglia also increasingly express CD68 [136], a phagocytosis protein that is scarcely detected in normal microglia but is robustly detected in plaqueassociated microglia [137]. In other words, the microglial gene expression profiles observed with natural aging are similar to those observed in neurodegenerative disease models, although less pronounced.…”

The multifaceted nature of amyloid precursor protein and its proteolytic fragments: friends and foes

“…More recently, DR6 has been shown to contribute to the process of axonal pruning triggered by sensory deprivation via whisker trimming in adult mice, an example of experience-dependent axonal plasticity [77], and to complex with the p75 neurotrophin receptor [p75(NTR)], a known mediator of Aβ-induced neurotoxicity, to trigger neuronal cell death [50]. However, recent studies have revised the conclusions to exclude the requirement of β-secretase activity in DR6’s functions, and to highlight the C-terminal portion of the APP ectodomain containing the E2 sequence in DR6’s interaction with APP [57, 97]. …”