A DR6/p75NTR complex is responsible for b-amyloid-induced cortical neuron death

Cell Death Dis. 2013 Apr 4;4:e579.

Yinghui Hu, Xinhua Lee, Zhaohui Shao, Bang Jian Gong, R Blake Pepinsky, and Sha Mi*

Biogenidec Inc., 14 Cambridge Center, Cambridge MA, 02142

 

*Corresponding Author:

Sha Mi, PhD

Department of Discovery Neurobiology

Biogenidec Inc.,

14 Cambridge Center,

Cambridge, MA 02142

Tel: 617 679 3843

Fax: 617 679 3148

Email: sha.mi@biogenidec.com

 

Abstract

The p75NTR neurotrophin receptor (p75NTR) is a known mediator of b-amyloid (Ab)-induced neurotoxicity implicated in Alzheimer’s disease (AD).  Here, we demonstrate that 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 up-regulated 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.

PMID: 23559013

 

Summary:

we have discovered that DR6 and p75NTR form a receptor complex that induces neuronal death upon binding of Aβ42.  Studies using cortical neurons isolated from p75NTR and DR6 null mice reveal that both p75NTR and DR6 contribute to Aβ-induced neurotoxicity as loss of either death receptor prevented the killing. The role DR6 plays in mediating neurotoxicity of Aβ42 with p75NTR may account for the variability reported by others in elucidating a death signal as cells lacking DR6 would not be responsive. Blocking the interaction between DR6 and p75 NTR represents a promising therapeutic target for AD.  

Sha Mi-1

 

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