Tumor necrosis factor receptor superfamily member 21 (DR6) and amyloid-beta precursor protein (APP) extracellular interface (DR6/APP interface)

The Death receptor 6 (DR6) and amyloid-beta precursor protein (APP) extracellular interface is a specific protein-protein interaction (PPI) that mediates neuronal death and axonal degeneration. This interaction involves the binding of an N-terminal fragment of APP (N-APP), which is produced by the proteolytic cleavage of APP, to the extracellular cysteine-rich domains of DR6 (also known as Tumor necrosis factor receptor superfamily member 21 or TNFRSF21) [Nikolaev et al., 2009, Nature]. Upon binding, DR6 initiates a pro-apoptotic signaling pathway that activates caspase-6 in the axon and caspase-3 in the cell body, leading to structural breakdown and cell death. This pathway has been implicated in the pathogenesis of Alzheimer's disease, where elevated levels of amyloid-related fragments may drive excessive axonal pruning and synapse loss [Kallop et al., 2014, Journal of Neuroscience]. Therapeutic strategies targeting this interface aim to disrupt the N-APP/DR6 binding using monoclonal antibodies or small molecule inhibitors to provide neuroprotection. However, because DR6 is also involved in regulating immune cell activation and lymphoid organ development, systemic inhibition may pose risks of immune-related side effects [Liu et al., 2001, Immunity].

Other names

TNFRSF21/APP complexN-APP/DR6 interactionDeath receptor 6/Amyloid precursor protein interfaceN-terminal Amyloid Precursor Protein/Death Receptor 6 complex

Inhibition of the protein-protein interaction between the N-terminal fragment of amyloid-beta precursor protein (N-APP) and death receptor 6 (DR6) to prevent caspase-mediated axonal degeneration and neuronal apoptosis [Nikolaev et al., 2009, Nature].