RETRACTED ARTICLE: APP binds DR6 to trigger axon pruning and neuron death via distinct caspases

Abstract

Naturally-occurring axonal pruning and neuronal cell death help sculpt neuronal connections during development, but their mechanistic basis remains poorly understood. We report that Amyloid Precursor Protein (APP) and Death Receptor 6 (DR6) activate a widespread caspase-dependent self-destruction program. DR6 is broadly expressed by developing neurons, and is required for normal cell body death and axonal pruning both in vivo and after trophic factor deprivation in vitro. Unlike neuronal cell body apoptosis, which requires caspase-3, we show that axonal degeneration requires caspase-6, which is activated in a punctate pattern that parallels the pattern of axonal fragmentation. DR6 is activated locally by an inactive surface ligand(s) that is released in active form upon trophic factor deprivation, and we identify APP as a DR6 ligand. Trophic factor deprivation triggers shedding of surface APP in a beta-secretase (BACE)-dependent manner. Loss- and gain-of-function studies support a model in which a cleaved amino-terminal fragment of APP (N-APP) binds DR6 and triggers degeneration. Genetic support is provided by a common neuromuscular junction phenotype in mutant mice. Our results indicate that APP and DR6 are components of a neuronal self-destruction pathway, and suggest that an extracellular fragment of APP, acting via DR6 and caspase-6, contributes to Alzheimer’s disease.

The secreted Alzheimer-related amyloid precursor protein fragment has an essential role inC. elegans

“…Here, we present hypothetical models as to how sAPL-1 signaling influences metabolic and developmental pathways. Together, with previous findings in mammals that the extracellular domain of mammalian APP (sAPP) binds to a death-receptor, 2 our findings support the model that sAPP signaling affects critical biological processes.…”

New insights into apoptosis signaling by Apo2L/TRAIL

“…Extensive studies on TNFR1, Fas, DR4 and DR5, with their respective cognate ligands, TNF-a (TNFSF2), Fas ligand (FasL or TNFSF6) and Apo2L/TRAIL (TNFSF10), have been reported in the literature. DR6 has recently emerged as a crucial component of a neuronal self-destruction pathway associated with Alzheimer's disease (Nikolaev et al, 2009). The extracellular fragment of the b-amyloid precursor protein (N-APP), characteristic to Alzheimer's brain pathology, binds DR6 and triggers neuronal degeneration through activation of caspase-6.…”

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

“…However, in addition to this classical role, caspases are also involved in non-apoptotic processes 84 . In the brain in particular, activation of the 'executioner' caspases has been observed in events associated with learning and memory such as synaptic plasticity and LTP, as well as the developmental pruning of axons [85][86][87][88] . These findings challenge the view of caspases as the final executioners of cell death and suggest that the role of these enzymes in neurodegeneration might be more upstream in signalling pathways, where they could mediate early neuronal dysfunction.…”

“…Caspases can also be activated by disturbances of developmental and synaptic plasticity signals such as axonal pruning or LTP [85][86][87][88]102 . In these non-apoptotic paradigms, caspase activation is usually contained in a well-defined subcellular compartment such as the synapse, and the active executioner caspases are kept under tight control by endogenous inhibitor proteins or through degradation by the proteasome 88,103 .…”