Abstract
The p75 neurotrophin receptor (p75NTR) is a known mediator of β-amyloid (Aβ)-induced neurotoxicity implicated in Alzheimer's disease (AD). Here, we demonstrate that death receptor 6 (DR6) binds to p75NTR and is a component of the p75NTR signaling complex responsible for Aβ-induced cortical neuron death. Cortical neurons isolated from either DR6 or p75NTR null mice are resistant to Aβ-induced neurotoxicity. Blocking DR6 function in cortical neurons by anti-DR6 antibodies that block the binding of DR6 to p75NTR receptor complex or by a dominant negative DR6 construct lacking the cytoplasmic signaling death domain attenuates Aβ-induced caspase 3 activation and cell death. DR6 expression is upregulated in AD cortex and correlates with elevated neuronal death. Targeting the disruption of the DR6/p75NTR complex to prevent Aβ cytotoxicity represents a new approach for the treatment of neurodegenerative disorders such as AD.
Highlights
Anti-death receptor 6 (DR6) antibody that blocks the formation of the DR6/p75NTR receptor complex significantly reduces Ab-induced neurotoxicity
We show that DR6 is expressed in adult cortical neurons and is upregulated in the Alzheimer’s disease (AD) brain
We discovered that DR6 forms a receptor complex with p75NTR that mediates Ab-induced neurotoxicity in cortical neurons
Summary
Tumor necrosis factor receptor (TNFR) superfamily members, which have roles in immunological and oncological diseases,[2,3] have recently emerged as drug targets for the treatment of neurodegenerative diseases such as Alzheimer’s and central nervous system (CNS) demyelination diseases.[4,5,6] A subset of the TNFR superfamily, the death receptors, contains four highly conserved cysteine-rich regions in their ectodomain and a cytoplasmic death domain that upon receptor oligomerization activates diverse downstream targets, including caspases.[7,8] Eight death receptors have been identified and each regulates cell death in selected cell populations:[8,9] Fas ( known as death receptor 2, CD95, and APO-1), TNFR1 (tumor necrosis factor receptor 1), TRAMP ( known as death receptor 3), TRAILR1 (TNFrelated apoptosis-inducing ligand receptor 1), TRAILR2, DR6 (death receptor 6), ectodermal dysplasia receptor, and p75NTR (p75 neurotrophin receptor). P75NTR forms a receptor complex with sortilin that binds pro-nerve growth factor to induce neuronal cell death.[6,11] p75NTR forms a tripartite complex with NogoR (Nogo receptor) and LINGO-1 (Leucine-rich repeat and Ig domain containing NogoR interacting protein 1) to inhibit axon outgrowth.[12] In addition, p75NTR has been shown to bind. Ab precursor protein in the absence of trophic factors through activation of the caspase 6 and casp[6] signaling pathway.[4] DR6 mediates oligodendrocyte cell death during development.[5] Here, we demonstrate that DR6 forms a receptor complex with p75NTR to induce cortical neuron death.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
