N-APP binds DR6 to cause axon pruning and neuron death via distinct caspases

By A. Nikolaev, Todd McLaughlin, D. O’Leary, M. Tessier-Lavigne. Nature, 2009

1,053 citations recorded by the source corpus.

Naturally occurring axonal pruning and neuronal cell death help to sculpt neuronal connections during development, but their mechanistic basis remains poorly understood. Here we report that β-amyloid precursor protein (APP) and death receptor 6 (DR6, also known as TNFRSF21) 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 an active form after trophic-factor deprivation, and we identify APP as a DR6 ligand. Trophic-factor deprivation triggers the shedding of surface APP in a β-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.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/f336104230299ed481d3b7229ca0f74dc1a4c228

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Citations in the corpus

ADAM10 is the physiologically relevant, constitutive α‐secretase of the amyloid precursor protein in primary neurons (2010, background): “…secreted form of APP (APPsa), which has been reported to have neurotrophic and neuroprotective properties (Furukawa et al, 1996; Meziane et al, 1998; Stein et al, 2004), whereas the slightly shorter form (APPsb) generated by b-secretase seems to have a proapoptotic function (Nikolaev et al, 2009).”
A review on Alzheimer’s disease pathophysiology and its management: an update (2015, background): “As discussed in the previous reviews about the role of caspase, enzymes of cysteine family of proteases, in the apoptotic pathways [105].”
Therapeutics of Alzheimer's disease: Past, present and future. (2014, background): “At least 7 caspases (caspases-1, 2, 3, 6, 8, 9, and 12) are implicated in Ab mediated neuronal death, of which, caspase 6 is the best known (Nikolaev et al., 2009).”
Amyloid Precursor Protein Processing and Alzheimer’s Disease (2011, background): “Combined with work suggesting growth factor deprivation can trigger APP cleavage by BACE1 and activate DR6 (Nikolaev et al. 2009), this line of investigation is a very interesting twist on the primacy of APP.”
Alzheimer’s disease: experimental models and reality (2017, background): “These additional APP cleavage products are also capable of causing toxicity independent of Aβ [45, 105].”
The amyloid hypothesis for Alzheimer’s disease: a critical reappraisal (2009, background): “The recent data showing that the extracellular domain of APP may have a role in axonal resculpting is an encouraging start in this direction (Nikolaev et al. 2009).”
APP processing in Alzheimer's disease (2011, neutral): “neuronal cell death [94].”
Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020, background): “In contrast, N-terminal fragment of APP derived from sAPPβ may be toxic, where it can bind death receptor 6 and mediate axonal pruning and neuronal cell death [26].”
Neuronal Cell Death. (2018, positive): “Dendritic pruning involving localized caspase-3 activity has been described as a form of “subcellular apoptosis” (312), and it is hypothesized that this potentially important physiological caspase function becomes aberrantly activated during the early stages of AD (144, 505).”
Programmed Cell Death in Animal Development and Disease (2011, positive): “Furthermore, chemical inhibition of Bax and knockdown of caspase-6 were also shown to inhibit sensory axon degeneration in Campenot chambers (Nikolaev et al., 2009).”
An Overview of APP Processing Enzymes and Products (2010, neutral): “A recent report demonstrated that sAPPβ is critically involved in pruning of synapses during development of both central and peripheral neurons (Nikolaev et al., 2009).”
Mechanisms Underlying Inflammation in Neurodegeneration (2010, neutral): “Inflammation-Dependent Pathology Ab formation and associated tauopathy appear to be sufficient to explain a cell-autonomous stress response in neurons, as recently supported by studies of the N-APP/DR6 mouse model of AD (Nikolaev et al., 2009).”