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Title page for ETD etd-08252014-160042

Type of Document Dissertation
Author Kraemer, Bradley Rhoads
Author's Email Address bradley.r.kraemer@Vanderbilt.edu
URN etd-08252014-160042
Title A Role for the p75NTR in Axonal Degeneration and Apoptosis Induced by Oxidative Stress
Degree PhD
Department Neuroscience
Advisory Committee
Advisor Name Title
Aaron B. Bowman Committee Chair
Bruce D. Carter Committee Member
Christine L. Konradi Committee Member
Scott W. Hiebert Committee Member
William H. Valentine Committee Member
  • neurotrophin
  • axon degeneration
  • p75NTR
  • apoptosis
  • oxidative stress
Date of Defense 2014-08-18
Availability unrestricted
The p75 Neurotrophin Receptor (p75NTR) is a critical regulator of axon pruning and apoptosis during neurodevelopment. Because the receptor has also been associated with many injurious or pathological conditions involving oxidative stress, this dissertation project aimed to investigate a role for p75NTR in neurodegeneration induced by oxidative injury. Our work revealed that receptor is activated by 4-hydroxy-2-nonenal (HNE), a lipid peroxidation product naturally generated during oxidative stress. Treatment of sympathetic neurons with HNE caused axonal degeneration and programmed cell death; however, neurons lacking p75NTR were significantly protected from these effects. HNE exposure was not associated with production of neurotrophins, and a ligand-blocking antibody failed to prevent HNE-induced apoptosis, thus suggesting that oxidative stress activates the receptor through a neurotrophin-independent mechanism. HNE exposure resulted in metalloprotease- and γ-secretase-dependent cleavage of p75NTR, and pharmacological inhibition of these proteolytic events protected neurons from HNE-induced apoptosis. Lastly, p75NTR-/- mice were resistant to oxidative injury caused by administration of 6-hydroxydopamine in vivo. Altogether, these findings indicate that in response to oxidative stress p75NTR is activated through a ligand-independent event which triggers cleavage of the receptor by a metalloprotease and γ-secretase, thereby leading to axonal degeneration and apoptosis.
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