Cellular and Molecular Neurobiology

, Volume 39, Issue 5, pp 577–590 | Cite as

Reductive Reprogramming: A Not-So-Radical Hypothesis of Neurodegeneration Linking Redox Perturbations to Neuroinflammation and Excitotoxicity

  • Timothy D. FoleyEmail author
Review Paper


Free radical-mediated oxidative stress, neuroinflammation, and excitotoxicity have long been considered insults relevant to the progression of Alzheimer’s disease and other aging-related neurodegenerative disorders (NDD). Among these phenomena, the significance of oxidative stress and, more generally, redox perturbations, for NDD remain ill-defined and unsubstantiated. Here, I argue that (i) free radical-mediated oxidations of biomolecules can be dissociated from the progression of NDD, (ii) oxidative stress fails as a descriptor of cellular redox states under conditions relevant to disease, and (iii) aberrant upregulation of compensatory reducing activities in neural cells, resulting in reductive shifts in thiol-based redox potentials, may be an overlooked and paradoxical contributor to disease progression. In particular, I summarize evidence which supports the view that reductive shifts in the extracellular space can occur in response to oxidant and inflammatory signals and that these have the potential to reduce putative regulatory disulfide bonds in exofacial domains of the N-methyl-d-aspartate receptor, leading potentially to aberrant increases in neuronal excitability and, if sustained, excitotoxicity. The novel reductive reprogramming hypothesis of neurodegeneration presented here provides an alternative view of redox perturbations in NDD and links these to both neuroinflammation and excitotoxicity.


Excitotoxicity Neurodegenerative disease Neuroinflammation Oxidative stress Protein thiols Redox signaling Reductive stress 



Alzheimer’s disease


Amyotrophic lateral sclerosis


β-Secretase 1






Reduced glutathione


Oxidized glutathione


Interleukin 1-β




Neurodegenerative disease




Parkinson’s disease




Reactive nitrogen oxide species


Reactive oxygen species


Superoxide dismutase-1


Tumor necrosis factor-α




Thioredoxin reductase


Thioredoxin-interacting protein


Compliance with Ethical Standards

Conflict of interest

The author declares that he has no conflicts of interest.

Ethical Approval

This article is a review and, as such, does not contain any newly reported studies with human participants or animals performed by the author.


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Chemistry and Neuroscience ProgramUniversity of ScrantonScrantonUSA

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